6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations

ABSTRACT

This invention describes the new 6-alkenyl- and 6-alkinyl-epothilone derivatives of general formula I 
                         
in which R 1a , R 1b , R 2a , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , A, Y, D, E, G, Y and Z are as defined in the specification. The compounds are useful in treating malignant tumours, for example, ovarian, stomach, colon, breast, adeno-, head and neck carcinomas, acute lymphocytic and myelocytic leukemia. In addition, these compounds are suitable for anti-angiogenesis therapy as well as for treatment of chronic inflammatory diseases such as psoriasis and arthritis. Methods of use and preparation of the compounds are also described.

This application is a 371 National Phase application of PCT/IB00/000657,filed May 1, 2000.

BACKGROUND OF THE INVENTION

Höfle et al. describe the cytotoxic action of the natural substancesepothilone A (R=hydrogen) and epothilone B (R=methyl) of the followingformula:

in, e.g., Angew. Chem. [Applied Chem.], 1996, 108, 1671–1673. Because oftheir in-vitro selectivity for breast cell lines and intestinal celllines and their significantly higher activity againstP-glycoprotein-forming multiresistant tumor lines in comparison to taxolas well as their physical properties that are superior to those oftaxol, e.g., a water solubility that is higher by a factor of 30, thisnovel structural class is especially advantageous for the development ofa pharmaceutical agent for treating malignant tumors.

The natural substances are not sufficiently stable either chemically ormetabolically for the development of pharmaceutical agents. To eliminatethese drawbacks, modifications to the natural substance are necessary.Such modifications are possible only with a total-synthesis approach andrequire synthesis strategies that make possible a broad modification ofthe natural substance. The purpose of the structural changes is also toincrease the therapeutic range. This can be done by improving theselectivity of the action and/or increasing the active strength and/orreducing undesirable toxic side-effects, as they are described in Proc.Natl. Acad. Sci. USA 1998, 95, 9642–9647.

The total synthesis of epothilone A is described by Schinzer et al. inChem. Eur. J. 1996, 2, No. 11, 1477–1482 and in Angew. Chem. 1997, 109,No. 5, pp. 543–544). Epothilone derivatives were already described byHöfle et al. in WO 97/19086. These derivatives were produced startingfrom natural epothilone A or B. Also, epothilones C and D (double bondbetween carbon atoms 12 and 13: epothilone C=deoxyepothilone A;epothilone D=deoxyepothilone B) are described as possible startingproducts for this purpose.

Another synthesis of epothilone and epothilone derivatives was describedby Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170–172. Thesynthesis of epothilone A and B and several epothilone analogues wasdescribed in Nature, Vol. 387, 1997, pp. 268–272; and the synthesis ofepothilone A and its derivatives was described in J. Am. Chem. Soc.,Vol. 119, No. 34, 1997, pp. 7960–7973 as well as the synthesis ofepothilone A and B and several epothilone analogues in J. Am. Chem.Soc., Vol. 119, No. 34, 1997, pp. 7974–7991 also by Nicolaou et al.

Nicolaou et al. also describe in Angew. Chem. 1997, 109, No. 19, pp.2181–2187 the production of epothilone A analogues using combinativesolid-phase synthesis. Several epothilone B analogues are also describedthere.

Epothilone derivatives, in some cases also epothilone C and D, are alsodescribed in patent applications WO 99/07692, WO 99/02514, WO 99/01124,WO 99/67252, WO 98/25929, WO 97/19086, WO 98/38192, WO 99/22461 and WO99/58534.

In the epothilone derivatives previously known, no alkenyl, alkinyl orepoxy radical was provided on carbon atom 6 (see the above formula) ofthe epothilone skeleton.

SUMMARY OF THE INVENTION

An object of this invention was to make available new epothilonederivatives, which are both chemically and metabolically stable enoughfor the development of pharmaceutical agents and which are superior tonatural derivatives in terms of their therapeutic range, theirselectivity of action and/or undesirable toxic side-effects and/or theiractive strength.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

Included in the invention are new epothilone derivatives and compoundsof general formula I,

in which

-   -   R^(1a), R^(1b) are the same or different and mean hydrogen,        C₁–C₁₀ alkyl, C₆–C₁₂ aryl or C₇–C₂₀ aralkyl, all optionally        substituted, or together a —(CH₂)_(m)— group with m=1, 2, 3, 4        or 5 or a —(CH₂)—O—(CH₂)— group,    -   R^(2a) means hydrogen, C₁–C₁₀ alkyl, C₁–C₁₂ aryl or C₇–C₂₀        aralkyl, all optionally substituted,        —(CH₂)_(ra)—C≡C—(CH₂)_(pa)—R^(26a),        —(CH₂)_(ra)—C═C—(CH₂)_(pa)—R^(26a),

-   -   R^(2b) means —(CH₂)_(rb)—C≡C—(CH₂)_(pb)—R^(26b),        —(CH₂)_(rb)—C═C—(CH₂)_(pb)—R^(26b),

-   -   n means 0 to 5,    -   ra, rb are the same or different and mean 0 to 4,    -   pa, pb are the same or different and mean 0 to 3,    -   R^(3a) means hydrogen, C₁–C₁₀ alkyl, C₆–C₁₂ aryl, or C₇–C₂₀        aralkyl, all optionally substituted    -   R¹⁴ means hydrogen, OR^(14a), Hal,    -   R^(3b) means OH or OPG¹⁴,    -   R⁴ means hydrogen, C₁–C₁₀ alkyl, C₆–C₁₂ aryl, or C₇–C₂₀ aralkyl,        all optionally substitued Hal, OR²⁵, CN,    -   R²⁵ means hydrogen, a protective group PG⁵,    -   R^(26a), R^(26b) are the same or different and mean hydrogen,        C₁–C₁₀ alkyl, C₆–C₁₂ aryl, or C₁–C₂₀ aralkyl, all optionally        substituted, C₁–C₁₀ acyl, or, if pa or pb>0, additionally a        group OR²⁷,    -   R²⁷ means hydrogen, a protective group PG⁶,    -   R⁵ means hydrogen, C₁–C₁₀ alkyl, C₆–C₁₂ aryl, C₇–C₂₀ aralkyl,        all optionally substituted (CH₂)_(s)-T, whereby        -   s stands for 1, 2, 3 or 4,        -   T stands for OR²² or Hal,        -   R²² stands for hydrogen or a protective group PG⁴    -   R⁶, R⁷ each mean a hydrogen atom, or taken together an        additional bond or an oxygen atom,    -   G means a group X═CR⁸—, a bi- or tricyclic aryl radical,    -   R⁸ means hydrogen, halogen, CN, C₁–C₂₀ alkyl, C₆–C₁₂ aryl,        C₇–C₂₀ aralkyl, which can all be substituted,    -   X means an oxygen atom, two alkoxy groups OR²³, a        C₂–C₁₀-alkylene-α,ω-dioxy group, which can be straight-chain or        branched, H/OR⁹ or a grouping CR¹⁰R¹¹, whereby        -   R²³ stands for a C₁–C₂₀ alkyl radical, optionally            substituted        -   R⁹ stands for hydrogen or a protective group PG^(x),        -   R¹⁰, R¹¹ are the same or different and stand for hydrogen, a            C₁–C₂₀ alkyl, C₆–C₁₂ aryl, or C₇–C₂₀ aralkyl radical, all            optionally substituted, or R¹⁰ and R¹¹ together with the            methylene carbon atom jointly stand for a 5- to 7-membered            carbocyclic ring,    -   D-E means a group —CH₂—CH₂—, —O—CH₂—,    -   A-Y means a group O—C(═O), O—CH₂, CH₂C(═O), NR²⁹—C(═O),        NR²⁹—SO₂,        -   R²⁹ means hydrogen, C₁–C₁₀ alkyl,    -   Z means an oxygen atom or H/OR¹², whereby        -   R¹² is hydrogen or a protective group PG^(z),    -   Hal means halogen, preferably fluorine, chlorine, bromine or        iodine.

The production of the new epothilone derivatives and compounds can beperformed by linkage of three partial fragments A_(f), B_(f) and C_(f)which process is a further aspect of the invention. The interfacesbetween the fragments are as indicated by the three lines crossing bandsin general formula I′.

A means a C₁–C₆ fragment (epothilone numbering system) of generalformula A-1 or A-2

in which

-   -   R^(1a′), R^(1b′), R^(2a′) and R^(2b′) have the meanings already        mentioned for R^(1a), R^(1b), R^(2a) and R^(2b) and    -   R¹³ means CH₂OR^(13a), CH₂-Hal, CHO, CO₂R^(13b), COHal,    -   R^(14′) means hydrogen, OR^(14a), Hal, OSO₂R^(14b),    -   R^(13a), R^(14a) mean hydrogen, SO₂-alkyl, SO₂-aryl, SO₂-aralkyl        or together a —(CH₂)₀— group or together a CR^(15a)R^(15b)        group,    -   R^(13b), R^(14b) mean hydrogen, C₁–C₂₀ alkyl, C₆–C₁₂ aryl,        C₇–C₂₀ aralkyl, each optionally substituted    -   R^(15a), R^(15b) are the same or different and mean hydrogen,        C₁–C₁₀ alkyl, aryl, C₇–C₂₀ aralkyl or together a —(CH₂)_(q)        group,    -   o means 2 to 4,    -   q means 3 to 6,    -   R³⁰ means hydrogen,    -   R³¹ means hydroxyl, or    -   R³⁰, R³¹ together mean an oxygen atom or a C₂–C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched, or    -   R³⁰, R³¹ independently mean a C₁–C₁₀ alkoxy group,    -   including all stereoisomers as well as their mixtures, and

free hydroxyl groups in R¹³, R¹⁴ and R³¹ can be etherified oresterified, free carbonyl groups can be ketalized in A-1 or A-2 and R¹³,converted into an enol ether or reduced, and free acid groups in A-1 orA-2 can be converted into their salts with bases.

B_(f) stands for a C₇–C₁₂ fragment (epothilone numbering system) ofgeneral formula

in which

-   -   D, E, R^(3a′), R^(4′) and R^(5′) have the meanings already        mentioned for D, E, R^(3a), R⁴, and R⁵, and    -   V means an oxygen atom, two alkoxy groups OR¹⁷, a C₂–C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched or H/OR¹⁶,    -   W means an oxygen atom, two alkoxy groups OR¹⁹, a        C₂–C₁₀-alkylene-α,ω-dioxy group, which can be straight-chain or        branched or H/OR¹⁸,    -   R¹⁶, R¹⁸, independently of one another, mean hydrogen or a        protective group PG¹,    -   R¹⁷, R¹⁹, independently of one another, mean C₁–C₂₀ alkyl        optionally substituted,    -   C_(f) stands for a C13–C16 fragment (epothilone numbering        system) of general formula

in which

-   -   G′ means a group X═CR^(8′)—, a bicyclic or tricylic aryl        radical,    -   R^(8′) has the meaning already mentioned in general formula I        for R⁸, and    -   R^(7′) means a hydrogen atom,    -   R²⁰ means halogen, N₃, NHR²⁹, a hydroxy group, a protected        hydroxy group O—PG², a protected amino group NR²⁹PG², a C₁–C₁₀        alkylsulfonyloxy group, which optionally can be perfluorinated,        a benzoyloxy group that is optionally substituted by C₁–C₄        alkyl, nitro, chlorine or bromine, an NR²⁹SO₂CH₃ group, an        NR²⁹C(═O)CH₃ group, a CH₂—C(═O)—CH₃ group,    -   R²¹ means a hydroxy group, halogen, a protected hydroxy group        OPG³, a phosphonium halide radical. PPh₃ ⁺Hal⁻(Ph=phenyl; Hal=F,        Cl, Br, I), a phosphonate radical P(O)(OQ)₂ (Q=C₁–C₁₀ alkyl or        phenyl) or a phosphine oxide radical P(O)Ph₂ (Ph=phenyl),    -   X means an oxygen atom, two alkoxy groups OR²³, a C₂–C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched, H/OR⁹ or a grouping CR¹⁰R¹¹, whereby        -   R²³ stands for a C₁–C₂₀ alkyl radical,        -   R⁹ stands for hydrogen or a protective group PG³,        -   R¹⁰, R¹¹ are the same or different and stand for hydrogen, a            C₁–C₂₀ alkyl, C₆–C₁₂ aryl, or C₇–C₂₀ aralkyl radical, each            optionally substituted, or R¹⁰ and R¹¹ together with the            methylene carbon atom commonly stand for a 5- to 7-membered            carbocyclic ring.

As alkyl groups R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R⁴, R⁵, R⁸, R¹⁰,R¹¹, R^(13a), R^(13b), R^(14a), R^(14b), R^(15a), R^(15b), R¹⁷, R¹⁹,R²³, R^(26a), R^(26b), R^(28a), R^(28b) and R²⁹ , straight-chain orbranched-chain alkyl groups with 1–20 carbon atoms can be considered,such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.

Alkyl groups R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R⁴, R⁵, R⁸, R¹⁰,R¹¹, R^(13a), R^(13b), R^(14a), R^(14b), R^(15a), R^(15b), R¹⁷, R¹⁹,R²³, R^(26a), R^(26b), R^(28a) and R^(28b) can be perfluorinated orsubstituted by 1–5 halogen atoms, hydroxy groups, C₁–C₄ alkoxy groups,C₆–C₁₂ aryl groups (which can be substituted by 1–3 halogen atoms).

As aryl radicals above and below, particularly R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R⁴, R⁵, R⁸, R¹⁰, R¹¹, R^(13a), R^(13b), R^(14a),R^(14b), R^(15a), R^(15b), R^(26a), R^(26b), R^(28a) and R^(28b),substituted and unsubstituted carbocyclic or heterocyclic radicals withone or more heteroatoms, such as, e.g., phenyl, naphthyl, furyl,thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl,pyrazinyl, quinolyl, thiazolyl, benzothiazolyl and benzoxazolyl, whichcan be substituted in one or more places by halogen, OH, O-alkyl, CO₂H,CO₂-alkyl, —NH₂, —NO₂, —N₃, —CN, C₁–C₂₀ alkyl, C₁–C₂₀ acyl, C₁–C₂₀acyloxy groups, are suitable examples.

As bi- and tricyclic aryl radicals G or G′, substituted andunsubstituted, carbocyclic or heterocyclic radicals with one or moreheteroatoms, such as, e.g., naphthyl, anthryl, benzothiazolyl,benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl,benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl,benzotriazolyl, dihydroindolyl, which can be substituted in one or moreplaces by halogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NH₂, —NO₂, —N₃, —CN,C₁–C₂₀ alkyl, C₁–C₂₀ acyl, C₁–C₂₀ acyloxy groups, are suitable.

The aralkyl groups in R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R⁴, R⁵,R⁸, R¹⁰, R¹¹, R^(13a), R^(13b), R^(14a), R^(14b), R^(15a), R^(15b),R^(26a), R^(26b), R^(28a) and R^(28b) can contain in the ring(s) up to14 C atoms, preferably 6 to 10, and in the alkyl chain 1 to 8,preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl,phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyland pyridinylpropyl are suitable. The rings can be substituted in one ormore places by halogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NO₂, —N₃, —CN,C₁–C₂₀ alkyl, C₁–C₂₀ acyl, C₁–C₂₀ acyloxy groups.

The alkoxy groups that are contained in R³⁰, R³¹ and X in generalformula I are in each case to contain 1 to 20 carbon atoms, wherebymethoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups arepreferred.

As representatives of all the protective groups PG (i.e., each of the PGgroups including those with a superscript), alkyl- and/oraryl-substituted silyl, C₁–C₂₀ alkyl, C₄–C₇ cycloalkyl, which inaddition can contain an oxygen atom in the ring, aryl, C₇–C₂₀ aralkyl,C₁–C₂₀ acyl, aroyl and C₁–C₂₀ alkoxycarbonyl can be mentioned. Otherprotective groups are known in the art and can be used as known.

As alkyl, silyl and acyl radicals for protective groups PG, the radicalsthat are known to one skilled in the art are suitable. Preferred arealkyl or silyl radicals that can be easily cleaved from thecorresponding alkyl and silyl ethers, such as, for example, themethoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl,tetrahydrofuranyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radicalas well as alkylsulfonyl and arylsulfonyl radicals. As acyl radicals,e.g., formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl orbenzoyl, which can be substituted with amino and/or hydroxy groups, aresuitable.

As amino protective groups, the radicals that are known to one skilledin the art are suitable. For example, the Alloc-, Boc-, Z-, benzyl,f-Moc, Troc, Stabase or Benzostabase group can be mentioned.

Acyl groups PG can contain 1 to 20 carbon atoms, whereby formyl, acetyl,propionyl, isopropionyl and pivalyl groups are preferred.

Index m in the alkylene group that is formed from R^(1a) and R^(1b)preferably stands for 1, 2, 3 or 4.

The C₂–C₁₀ alkylene-α,ω-oxy group that is possible for R³⁰, R³¹, U, V, Wand X is preferably an ethyleneketal or neopentylketal group.

The compounds that are mentioned below are preferred according to theinvention:

-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R),3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-    8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-fluoro-2-(2-pyridyl)    ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8′-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R, 3S(E),7S,10R(RS),    1R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-Dihydroxy-10-(prop-2-in-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,(10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,    16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R_(,)3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S    10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S    10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S 10R,11R,12S    16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop)-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R, 12S    16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,    2S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-418-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16RS)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-11-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.10]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,1R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.10]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-    8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,1R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)-ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-methyl-2-(2-methythiazol-4-yl)ethenyl-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(2-oxacyclopropyl-1-ethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(2-oxacyclopropyl-1-ethyl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12-16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R(RS),8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5-trimethylene-9,13-dimethyl-7-(oxacyclopropylmethyl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R(RS),11R,12S,16R/S)-7,11-dihydroxy-10-(oxacyclopropylmethyl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8-trimethylene-12,16-dimethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxobicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-methyl-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-fluoro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-chloro-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-1′-(3-methyl-but-2-en-1-yl)-3-(2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),    7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-chloro-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,    16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),    7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-methyl-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13E/Z,16S(E))-4,8-dihydroxy-16-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione-   (1S/R,3S(E),7S,11R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(1-chloro-2-(2-methyloxazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione    Production of Partial Fragments A_(f):

The partial fragments (synthesis components) of general formula A-1 canbe produced starting from the precursors described in WO 99/07692, suchas, for example, A-I. This is further explained by way of example inDiagram 1.

Step a (A-I→A-II):

The hydroxyl group that is protected by PG⁷ in A-1 is released. Asprotective group PG⁷, the protective groups described above and that areknown to one skilled in the art, such as, e.g., the methoxymethyl,methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl,trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl, triiospropylsilyl, benzyl,para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl,isopropionyl, pivalyl, butyryl or benzoyl radicals, are suitable. Asurvey is found in, e.g., “Protective Groups in Organic Synthesis,”Theodora W. Green, John Wiley and Sons).

Preferred are those protective groups that can be cleaved under theaction of fluoride, such as, e.g., the trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, ortriisopropylsilyl radical.

Especially preferred are the tert-butyldimethylsilyl radical, thetriisopropylsilyl radical, and the tert-butyldiphenylsilyl radical.

As protective groups PG^(8a) and PG^(8b), the groups that are alreadymentioned for PG⁷ and together a —CR^(28a)R^(28b) group, in whichR^(28a) and R^(28b) can be the same or different and mean hydrogen,C₁–C₁₀ alkyl, aryl, C₇–C₂₀ aralkyl, are suitable.

Preferred are those —CR^(28a)R^(28b) protective groups, in which R^(28a)and R^(28b) mean C₁–C₈ alkyl, or R^(28a) means hydrogen and R^(28b)means aryl.

Especially preferred is a —C(CH₃)₂ group.

Protective group PG⁷ is cleaved according to a process that is known toone skilled in the art. This is a silyl ether, thus suitable for thecleavage is the reaction with fluorides, such as, for example,tetrabutylammonium fluoride, hydrogen fluoride-pyridine complex,potassium fluoride or the use of dilute mineral acids, the use ofcatalytic amounts of acids, such as, e.g., para-toluenesulfonic acid,para-toluenesulfonic acid-pyridinium salt, camphorsulfonic acid inalcoholic solutions, preferably in ethanol or isopropanol.

Step b (A-II→A-III):

The oxidation of the primary alcohol in A-II to aldehyde A-III iscarried out according to the methods that are known to one skilled inthe art. For example, oxidation with pyridinium chlorochromate,pyridinium dichromate, chromium trioxide-pyridine complex, oxidationaccording to Swern or related methods, e.g., with use of oxalyl chloridein dimethyl sulfoxide, the use of Dess-Martin periodinane, the use ofnitrogen oxides, such as, e.g., N-methyl-morpholino-N-oxide in thepresence of suitable catalysts, such as, e.g., tetrapropylammoniumperruthenate in inert solvents, can be mentioned. Preferred is theoxidation according to Swern, as well as withN-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate.

Step c (A-III→A-IV):

The reaction of aldehydes A-III to alcohols of formula A-IV is carriedout with organometallic compounds of theoretical formula M—CHR₂R^(2a′),in which M stands for indium, an alkali metal, preferably lithium or adivalent metal MX, in which X represents a halogen, and radical R^(2a′)has the above-mentioned meanings. As a divalent metal, magnesium andzinc are preferred; as halogen, X is preferably chlorine, bromine andiodine.

Step d (A-IV→A-V):

The oxidation of the secondary alcohol in A-IV to ketone A-V is carriedout according to the conditions that are mentioned under step b).Preferred is the oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate.

Step e (A-V→A-VI):

For optional introduction of a radical R^(2b′), which, except forhydrogen, can have the already mentioned meanings, the ketone of generalformula A-V is converted into the enolate with M in the meaning of thecounter-cation with use of strong bases, such as preferably lithiumdiisopropylamide.

Step f (A-VI→A-VII):

The enolate of formula A-VI is reacted with a compound of generalformula X—R^(2b′), in which X represents a halogen or another leavinggroup, such as, for example, an alkylsulfonate or arylsulfonate. Ashalogen, X is preferably chlorine, bromide and iodine.

The partial fragments (synthesis components) of general formula A-2 canbe produced by known methods, such as described in Angew. Chemie 1996,108, 2976–2978. Another process is shown in Diagram 2:

Step a (A-VIII→A-IX):

The oxidation of the primary alcohol in A-VIII to aldehyde A-IX iscarried out according to the methods that are described for Diagram 1,step b. The oxidation according to Swern and withN-methyl-morpholino-N-oxide with use of tetrapropylammonium perruthenateis preferred.

Step b (A-IX→A-X):

The carbonyl group in A-IX can optionally be converted into a ketalaccording to the methods that are known to one skilled in the art.

Step c (A-X→A-XI):

The hydroxyl group that is protected in A-X by PG⁹ is released. Asprotective group PG⁹, the protective groups that are described underDiagram 1, step a are suitable. Preferred are those protective groupsthat can be cleaved under the action of fluoride, such as, e.g., thetrimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,tribenzylsilyl, or triisopropylsilyl radical.

Especially preferred is the tert-butyldimethylsilyl radical, thetriisopropylsilyl radical and the tert-butyldiphenylsilyl radical.

Step d (A-XI→A-XII):

The oxidation of the primary alcohol in A-IX to aldehyde A-XII iscarried out according to the methods that are described for Diagram 1,step b. The oxidation according to Swern and withN-methyl-morpholino-N-oxide with use of tetrapropylammonium perruthenateis preferred.

Step e (A-XII→A-XIII):

The introduction of radicals R^(2a′) and/or R^(2b′) and production ofketone A-XIII are carried out as described under Diagram 1 in steps c tof.

Production of Partial Fragments B_(f):

The partial fragments (synthesis components) of general formula B_(f)can be produced by known methods, such as described in WO 99/07692.

Production of Partial Fragments C_(f):

The partial fragments (synthesis components) of general formula C_(f)can be produced as described in DE 197 51 200.3, DE 199 07 480.1 and WO99/07692 as well as in PCT/EP00/01333 and Example 21.

Production of partial fragments A_(f), B_(f) and C_(f) and theircyclization to I is also carried out analogously to what is described inWO 99/07692 for numerous epothilone derivatives, with the differencethat in the known derivatives in 6-position, there is no unsaturatedradical. WO 99/07692 already confirms the general usability of thesynthesis principle that is described below for the compounds accordingto the invention. In addition, numerous synthesis components of generalformulas A_(f), B_(f) and C_(f) are described in WO 99/07692, withwhich, optionally in modified form in the case of the substitutionaccording to the invention at carbon 6, other compounds of generalformula I claimed here can be obtained. Synthesis components of generalformula C_(f), in which as R⁸, a halogen atom, especially a fluorine,chlorine or bromine atom, is present, are the subject of DE 199 07 480.1as well as PCT/EP00/01333.

Partial fragments of general formula AB

in which R^(1a′), R^(1b′), R^(2a′), R^(2b′), R^(3a′), R⁴, R⁵, R¹³, R¹⁴,R³⁰, R³¹, V and Z have the already mentioned meanings, and PG¹⁴′represents a hydrogen atom or a protective group PG, can be obtainedfrom the above-mentioned fragments A_(f) and B_(f) according to theprocess that is shown in Diagram 3.

Step aa (A_(f)+B_(f)→AB):

Compound B_(f), in which W has the meaning of an oxygen atom andoptionally present additional carbonyl groups are protected, isalkylated with the enolate of a carbonyl compound of general formulaA_(f). The enolate is produced by action of strong bases, such as, e.g.,lithium diisopropylamide, lithium hexamethyldisilazane at lowtemperatures.

Partial Fragments of General Formula BC

in which R^(3a), R⁴, R⁵, R⁶, R⁷, R²⁰, D, E, G and W have the alreadymentioned meanings, are obtained from previously described fragmentsB_(f) and C_(f) according to the process that is shown in Diagram 4.

Step ab (B_(f)+C_(f)→BC):

Compound C, in which R²¹ has the meaning of a Wittig salt, andoptionally present additional carbonyl groups are protected, isdeprotonated by a suitable base, such as, e.g., n-butyllithium, lithiumdiisopropylamide, potassium tert-butanolate, sodium orlithium-hexamethyldisilazide and reacted with a compound B_(f), in whichV has the meaning of oxygen, and W has the meaning of two alkoxy groupsOR¹⁹, a C₂–C₁₀-alkylene-α,ω-dioxy group, which can be straight-chain orbranched or has H/OR¹⁸.

Partial Fragments of General Formula ABC (AB+C_(f))

in which R^(1a′), R^(1b′), R^(2a′), R^(2b′), R^(3a), R⁴, R⁵, R⁶, R⁷,R¹³, R¹⁴, R³⁰, R³¹, D, E, G and Z have the meanings already mentioned,and PG^(14′) represents a hydrogen atom or a protective group PG, areobtained from the previously described fragments AB and C according tothe process that is shown in Diagram 5 and Diagram 6.

Step ac (AB+C_(f)→ABC):

Compound C_(f), in which R²¹ has the meaning of a Wittig salt, andoptionally present additional carbonyl groups are optionally protected,is deprotonated by a suitable base, such as, e.g., n-butyllithium,lithium diisopropylamide, potassium tert-butanolate, sodium orlithium-hexamethyldisilazide and reacted with a compound AB, in which Vhas the meaning of an oxygen atom.

Step ad (A_(f)+BC→ABC):

Compound BC, in which W has the meaning of an oxygen atom and optionallypresent additional carbonyl groups are protected, is alkylated with theenolate of a carbonyl compound of general formula A_(f). The enolate isproduced by action of strong bases, such as, e.g., lithiumdiisopropylamide, lithium hexamethyldisilazane at low temperatures.

Step ae (ABC-1→I):

Compounds ABC-1, in which R¹³ represents a carboxylic acid CO₂H and R²⁰represents a hydroxyl group or an amino group, are reacted according tothe methods that are known to one skilled in the art for the formationof large macrolides or macrolactams to compounds of formula I, in whichA-Y has the meaning of an O—(C═O) group or NR²⁹—C(═O) group. Forexample, preferred for lactone formation is the method that is describedin “Reagents for Organic Synthesis, Vol. 16, p. 353” with use of2,4,6-trichlorobenzoic acid chloride and suitable bases, such as, e.g.,triethylamine, 4-dimethylaminopyridine, sodium hydride. For example,preferred for the lactam formation is the reaction of the amino acid(R¹³ a carboxylic acid CO₂H and R²⁰ an NHR²⁹ group) withdiphenylphosphorylazide in the presence of a base.

Step af (ABC-1→I):

Compounds ABC-1, in which R¹³ represents a group CH₂OH and R²⁰represents a hydroxyl group, can be reacted preferably with use oftriphenylphosphine and azodiesters, such as, for example,azodicarboxylic acid diethyl ester, to compounds of formula I, in whichA-Y has the meaning of an O—CH₂ group.

Compounds ABC, in which R¹³ represents a group CH₂-Hal or CH₂OSO₂— alkylor CH₂OSO₂ aryl or CH₂OSO₂— aralkyl and R²⁰ represents a hydroxyl group,can be cyclized to compounds of formula I, in which A-Y has the meaningof an O—CH₂ group, after deprotonation with suitable bases, such as, forexample, sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünigbase, alkylhexamethyldisilazanes.

Step ag (ABC-2→1):

Compounds ABC-2, in which R³⁰ and R³¹ together represent an oxygen atomand R²⁰ represents an NR²⁹SO₂CH₃ group, can be cyclized at lowtemperatures to sulfonamide I, in which A-Y has the meaning of anNR²⁹SO₂ group, by action of strong bases, such as, e.g., lithiumdiisopropylamide, lithium hexamethyldisilazane.

Step ah (ABC-2→1):

Compounds ABC-2, in which R³⁰ and R^(31′) together represent an oxygenatom and R²⁰ represents an O—C(═O)CH₃ group, can be cyclized at lowtemperatures to lactone I, in which A-Y has the meaning of an O—C(═O)group, by action of strong bases, such as, e.g., lithiumdiisopropylamide, or alkali hexamethyldisilazane.

Step ah (ABC-2→I):

Compounds ABC-2, in which R³⁰ and R³¹ together represent an oxygen atomand R²⁰ represents a CH₂C(═O)CH₃ group, can be cyclized at lowtemperatures to lactone I, in which A-Y has the meaning of a CH₂C(═O)group by action of strong bases such as, e.g., lithium diisopropylamide,alkali hexamethyldisilazane.

Introduction of the Nitrogen Group for R²⁰:

Amino group NHR²⁹ can be introduced in the stage of the C_(f)-fragment,the BC-fragment or the ABC-fragment according to the methods that areknown to one skilled in the art. Preferred is the production from theazide (R²⁰=N₃), which is first converted into the phosphaimine accordingto the methods that are known to one skilled in the art, preferably withuse of a phosphine such as, for example, triphenylphosphine; thephosphaimine is then converted in the presence of water into the amine(R²⁰=NHR²⁹) that is optionally to be protected for the further course ofreaction. The introduction of the azide can be carried out with use ofthe Mitsunobu reaction in the presence of metal azides, preferablysodium or tin azide or by substitution of a suitable leaving group, suchas, for example, a chlorine, bromine or iodine atom, an alkylsulfonyloxygroup, a perfluorinated alkylsulfonyloxy group, an arylsulfonyloxy groupor an aralkylsulfonyloxy group by azides.

The flexible functionalization of described components A_(f), B_(f) andC_(f) also ensures a linkage sequence that deviates from theabove-described process and that leads to components ABC. Theseprocesses are listed in the following table:

Linkage Methods a Possible Linkages to e Prerequisites A_(f) + B_(f) →A_(f) − B_(f) a: Aldol (see Z = W = oxygen Diagram 3) B_(f) + C_(f) →B_(f) − C_(f) b: Wittig U = oxygen and R²¹ = (analogously to Wittigsalt, Diagram 4) phosphine oxide or e: McMurry phosphonate U = V =oxygen A_(f) + C_(f) → A_(f) − C_(f) C: Esterification R¹³ = CO₂R^(13b)or (e.g., 2,4,6- COHal and trichlorobenzoyl R²⁰ = hydroxyl chloride and4- dimethylamino pyridine) d: Etherification R¹³ = CH₂OH and R²⁰ =(e.g., according to hydroxyl or OSO₂- Mitsunobu) alkyl or OSO₂-aryl orOSO₂-aralkyl f. Amide formation R¹³ = CO₂R^(13b) or (e.g., with COHaland R²⁰ = (PhO)₂P(O)N₃) in the NHR²⁹ presence of a base in an inertsolvent g. Ketone R²⁰ = CH₂C(═O)CH₃ and formation by aldol R³⁰, R³¹ =oxygen reaction with a strong base. h. Sulfonamide R²⁰ = NR²⁹SO₂CH₃ andformation in the R³⁰, R³¹ = oxygen presence of a strong base. i. Amideformation R²⁰ = NR²⁹C(═O)CH₃ in the presence of and R³⁰, R³¹ = oxygen astrong base.

According to these processes, components A_(f), B_(f) and C_(f) can belinked as indicated in Diagram 7:

Free hydroxyl groups in I, A_(f), B_(f), C_(f), AB, BC, ABC can befurther functionally modified by etherification or esterification, freecarbonyl groups by ketalization, enol ether formation or reduction.

The invention relates to all stereoisomers of these compounds and alsomixtures thereof.

The invention also relates to all prodrug formulations of thesecompounds, i.e., all compounds that release in vivo a bioactive activeingredient component of general formula I.

Biological Actions and Applications of the New Derivatives:

The new compounds of formula I are valuable pharmaceutical agents. Theyinteract with tubulin by stabilizing microtubuli that are formed and arethus able to influence the cell-splitting in a phase-specific manner.Accordingly, the compounds find use in treating diseases or conditionsassociated with cell growth, division and/or proliferation. They haveparticular application with quick-growing, neoplastic cells, whosegrowth is largely unaffected by intercellular regulating mechanisms.Active ingredients having properties of this type, including thecompounds of this invention, are suitable for treating malignant tumors.As applications, there can be mentioned, for example, the therapy ofovarian, stomach, colon, adeno-, breast, lung, head and neck carcinomas,malignant melanoma, acute lymphocytic and myelocytic leukemia,particularly against tumors associated therewith. The compoundsaccording to the invention are additionally suitable owing to theirproperties for anti-angiogenesis therapy as well as for treatment ofchronic inflammatory diseases, such as, for example, psoriasis, multiplesclerosis or arthritis. The compounds of the invention have utilitiesanalogous to those for known epothilone derivatives, discussed above,but with the advantages discussed above and below. As with the knownepothilones, the new compounds can be administered for and in a manneranalogous to known drugs such as Taxol, but modified to take advantageof their particular superior properties thereover.

In other embodiments, to avoid uncontrolled proliferation of cellsand/or for better compatibility of medical implants, the new compoundsor pharmaceutical formulations containing them can be applied orintroduced into the polymer materials that are used for these purposes.

The compounds according to the invention can be used alone or incombination with other principles and classes of substances that can beused in tumor therapy to achieve additive or synergistic actions. Asexamples, there can be mentioned the combination with

-   -   Platinum complexes, such as, e.g., cis-platinum, carboplatinum,    -   intercalating substances, e.g., from the class of        anthracyclines, such as, e.g., doxorubicin or from the class of        anthrapyrazoles, such as, e.g., Cl-941,    -   substances that interact with tubulin, e.g., from the class of        vinca-alkaloids, such as, e.g., vincristine, vinblastine or from        the class of taxanes, such as, e.g., taxol, taxotere or from the        class of macrolides, such as, e.g., rhizoxin or other compounds,        such as, e.g., colchicine, combretastatin A-4, discodermolide        and its analogs,    -   DNA topoisomerase inhibitors, such as, e.g., camptothecin,        etoposide, topotecan, teniposide,    -   folate- or pyrimidine-antimetabolites, such as, e.g, lometrexol,        gemcitubin,    -   DNA-alkylating compounds, such as, e.g., adozelesin, dystamycin        A,    -   inhibitors of growth factors (e.g., of PDGF, EGF, TGFb, EGF),        such as, e.g., somatostatin, suramin, bombesin antagonists,    -   inhibitors of protein tyrosine kinases or protein kinases A or        C, such as, e.g., erbstatin, genistein, staurosporine,        ilmofosine, 8-Cl-cAMP,    -   antihormones from the class of antigestagens, such as, e.g.,        mifepristone, onapristone or from the class of antiestrogens,        such as, e.g., tamoxifen or from the class of antiandrogens,        such as, e.g., cyproterone acetate,    -   metastases-inhibiting compounds, e.g., from the class of        eicosanoids, such as, e.g., PGl₂, PGE₁, 6-oxo-PGE₁ as well as        their more stable derivatives (e.g., iloprost, cicaprost,        misoprostol),    -   inhibitors of oncogenic RAS proteins, which influence the        mitotic signal transduction, such as, for example, inhibitors of        the farnesyl-protein-transferase,    -   natural or synthetically produced antibodies, which are directed        against factors or their receptors, which promote tumor growth,        such as, for example, the erbB2 antibody.

The invention also relates to pharmaceutical agents that are based onpharmaceutically compatible compounds, i.e., compounds of generalformula I that are nontoxic in the doses used, optionally together withcommonly used adjuvants and vehicles.

In other embodiments, the compounds according to the invention can beencapsulated with liposomes or included in an α-, β- or γ-cyclodextrinclathrate.

According to methods of galenicals that are known in the art, thecompounds according to the invention can be processed intopharmaceutical preparations for enteral, percutaneous, parenteral orlocal administration. They can be administered in the form of tablets;coated tablets; gel capsules; granulates; suppositories; implants;injectable, sterile, aqueous or oily solutions; suspensions oremulsions; ointments; creams and gels, for example.

In this case, the active ingredient or ingredients can be mixed with theadjuvants that are commonly used in galenicals, such as, e.g., gumarabic, talc, starch, mannitol, methyl cellulose, lactose, surfactantssuch as Tweens or Myrj, magnesium stearate, aqueous or non-aqueousvehicles, paraffin derivatives, cleaning agents, dispersing agents,emulsifiers, preservatives and flavoring substances for taste correction(e.g., ethereal oils).

The invention thus also relates to pharmaceutical compositions that asactive ingredients contain at least one compound-according to theinvention. A dosage unit will preferably contain about 0.1–100 mg ofactive ingredient(s). In humans, the dosage of the compounds accordingto the invention is preferably approximately 0.1–1000 mg per day.

The examples below are used for a more detailed explanation of theinvention, without intending that it be limited to these examples.

The entire disclosure of all applications, patents and publications,cited above or below, and of corresponding German application Nos. 19921 086.1, filed 30 Apr. 1999, and 199 54 228.7, filed 4 Nov. 1999, arehereby incorporated by reference.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

Example 14S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dioneProduction of(4S(4R,5S,6S,10E/Z,13S,14E))-4-(β-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane;Variant I: Example 1a(3RS,4S)-4-(2-Methyl-3-hydroxy-8-(trimethylsilyl)-oct-7-in-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 6.33 g (34 mmol) of(4S)-4-(2-methyl-1-oxo-prop-2-yl)-2,2-dimethyl-[1,3]dioxane, which wasproduced analogously to the process described in DE 197 51 200.3, in 10ml of anhydrous tetrahydrofuran is mixed in portions under an atmosphereof dry argon with the solution of a total of 50 mmol of5-trimethylsilyl-pent-4-in-1-yl-magnesium bromide in tetrahydrofuran,allowed to heat to 60° C. and stirred for 1.5 hours. It is poured ontowater and extracted several times with ethyl acetate. The combinedorganic extracts are washed with water and saturated sodium chloridesolution and dried on sodium sulfate. The residue that was obtainedafter filtration and removal of the solvent is purified bychromatography on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate. 6.22 g (19 mmol, 56%) of thechromatographically separable 3R- and 3S-epimers of the title compoundand 1.35 g of(4S)-4-(2-methyl-1-hydroxy-prop-2-yl)-2,2-dimethyl-[1,3]dioxane areisolated in each case as a colorless oil.

¹H-NMR (CDCl₃): δ=0.14 (9H), 0.73+0.88 (3H), 0.91 (3H), 1.28–1.93 (12H),2.21–2.33 (2H), 3.40–3.72 (2H), 3.80–4.03 (3H) ppm.

Example 1b(4S)-4-(2-Methyl-3-oxo-8-(trimethylsilyl)-oct-7-in-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 6.22 g (19 mmol) of a mixture of the compounds, producedaccording to Example 1a, in 200 ml of anhydrous dichloromethane is mixedwith a molecular sieve (4A, about 20 pellets), 4.01 g ofN-methylmorpholino-N-oxide, 335 mg of tetrapropylammonium perruthenateand stirred for 16 hours at 23° C. under an atmosphere of dry argon. Itis concentrated by evaporation, the crude product that is obtained ispurified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 5.17 g (15.9 mmol, 84%) ofthe title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.15 (9H), 1.07 (3H), 1.13 (3H), 1.28–1.36 (1H), 1.33(3H), 1.41 (3H), 1.53–1.81 (3H), 2.22 (2H), 2.62 (2H), 3.85 (1H), 3.97(1H), 4.06 (1H) ppm.

Example 1c(4S(4R,5S,6S,10RS))-4-(5-Hydroxy-2,6-dimethyl-3-oxo-4-(4-(trimethylsilyl)-but-3-in-1-yl)-10-[[diphenyl(1,1-dimethylethyl)silyl]oxy]-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10RS))-4-(5-hydroxy-2,6-dimethyl-3-oxo-4-(4-(trimethylsilyl)-but-3-in-1-yl)-10-[[diphenyl(1,1-dimethylethyl)silyl]oxy]-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

The solution of 1.33 ml of diisopropylamine in 35 ml of anhydroustetrahydrofuran is cooled under an atmosphere of dry argon to −3.0° C.,mixed with 4.28 ml of a 2.4 molar solution of n-butyllithium in n-hexaneand stirred for another 15 minutes. At −78° C., the solution of 2.87 g(8.84 mmol) of the compound, produced according to Example 1c, in 35 mlof tetrahydrofuran is added in drops, and it is allowed to react for 1hour. Then, it is mixed slowly with the solution of 3.93 g (10.3 mmol)of (2S,6RS)-2-methyl-6-(tert-butyl-diphenylsilyloxy)-heptanal, which wasproduced analogously to the process that is described in DE 197 51200.3, in 35 ml of tetrahydrofuran, and it is poured into saturatedammonium chloride solution after 1 hour. It is diluted with water,extracted several times with ethyl acetate, the combined organicextracts are washed with saturated sodium chloride solution, dried onsodium sulfate and concentrated by evaporation in a vacuum. After columnchromatography on silica gel with a gradient system that consists ofn-hexane and ethyl acetate, 2.40 g (3.39 mmol, 38%) of title compound Aand 1.52 g (2.15 mmol, 24%) of diastereomer B are obtained in additionto starting material.

¹H-NMR (CDCl₃) of A: δ 0.16 (9H), 0.83 (3H), 1.00 (3H), 1.02 (3H), 1.04(9H), 1.10–1.77 (10H), 1.28 (3H), 1.31 (3H), 1.37 (3H), 1.83–2.03 (2H),2.19–2.38 (2H), 3.52 (1H), 3.62 (1H), 3.78–3.92 (2H), 3.98 (1H), 4.23(1H), 7.30–7.46 (6H), 7.67 (4H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.13 (9H), 0.86+0.92 (3H), 0.95–1.77 (16H), 1.03(9H), 1.21+1.25 (3H), 1.32 (3H), 1.40 (3H), 1.88–2.09 (2H), 2.26 (1H),2.39 (1H), 3.29–3.54 (2H), 3.77–3.90 (2H), 3.96 (1H), 4.18 (1H),7.31–7.46 (6H), 7.67 (4H) ppm.

Example 1d(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-3-oxo-4-(4-(trimethylsilyl)-5-(tetrahydro-2H-pyran-2-yloxy)-but-3-in-1-yl)-10-[[diphenyl(1,1-dimethylethyl)silyl]oxy]-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 2.35 g (3.32 mmol) of compound A, produced according toExample 1c, in 55 ml of anhydrous dichloromethane is mixed under anatmosphere of dry argon with 3.04 ml of 3,4-dihydro-2H-pyran, 0.67 g ofp-toluenesulfonic acid, and it is stirred for 48 hours at 23° C. It ispoured into a saturated sodium bicarbonate solution, the organic phaseis separated, and it is dried on sodium sulfate. After filtration andremoval of the solvent, the residue is chromatographed on fine silicagel with a mixture that consists of n-hexane and ethyl acetate. 2.29 g(2.89 mmol, 87%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.05 (9H), 0.88–2.15 (28H), 1.03 (9H) 1.41 (3H), 1.59(3H), 2.21–2.48 (1H), 3.31–4.53 (9H), 7.30–7.45 (6H), 7.69 (4H) ppm.

Example 1e(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-10-hydroxy-3-oxo-5-(tetrahydro-2H-pyran-2-yloxy)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 2.48 g (3.13 mmol) of the compound, produced accordingto Example 1d, in 25 ml of anhydrous tetrahydrofuran is mixed under anatmosphere of dry argon with 12.5 ml of a 1 molar solution oftetrabutylammonium fluoride in tetrahydrofuran, and it is stirred for 4hours at 23° C. It is mixed with saturated sodium bicarbonate solution,extracted several times with ethyl acetate, washed with saturated sodiumchloride solution and dried on sodium sulfate. The residue that isobtained after filtration and removal of the solvent is purified bychromatography on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate. 1.41 g (2.93 mmol, 94%) of the titlecompound is isolated as a colorless oil.

Example 1f(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-3,10-dioxo-5-(tetrahydro-2H-pyran-2-yloxy)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1b, 1.27 g (2.63 mmol) of the compound, producedaccording to Example 1e, is reacted, and after working-up andpurification, 1.14 g (2.38 mmol, 91%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.95–2.48 (29H), 0.98+1.01 (3H), 1.42 (3H), 2.13 (3H),3.29–3.47 (2H), 3.64–4.04 (4H), 4.20+4.32 (1H), 4.39+4.50 (1H) ppm.

Example 1g(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[Diphenyl(1,1-dimethylethyl)silyl]oxy]-5-(tetrahydro-2H-pyran-2-yloxy)-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

The suspension of 2.87 g (3.57 mmol) of(5E,3S)-[3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-S-(2-pyridyl)-pent-4-en-1-yl]-triphenyl-phosphoniumiodide, which was produced analogously to the process described in DE197 51 200.3, in 11 ml of anhydrous tetrahydrofuran, is mixed at 0° C.under an atmosphere of dry argon with 2.72 ml of a 1.6 M solution ofn-butyllithium in n-hexane and allowed to heat to 23° C. The solution of1.14 g (2.38 mmol) of the compound, produced according to Example 1f, in11 ml of tetrahydrofuran is slowly added in drops to the red solution,allowed to stir for 2 hours, poured onto saturated ammonium chloridesolution and extracted several times with ethyl acetate. The combinedorganic extracts are dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography on silica gel witha gradient system that consists of n-hexane and ethyl acetate, 860 mg(0.98 mmol, 41%) of the title compound is obtained in addition to 20%starting material.

¹H-NMR (CDCl₃)=0.82–2.41 (41H), 1.05 (9H), 2.00 (3H), 3.23–3.45 (2H),3.60–4.02 (3H), 4.08–4.51 (3H), 4.92–5.24 (1H), 6.16–6.76 (1H),6.92–7.08 (2H), 7.21–7.43 (6H), 7.49–7.72 (5H), 8.55 (1H) ppm.

Example 1h Variant I:(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-Hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1b, 482 mg (550 μmol) of the compound that isproduced according to Example 1g is reacted, and after working-up andpurification, 256 mg (401 μmol, 73%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.88–2.48 (35H), 1.42 (3H), 1.64+1.72 (3H), 2.08 (3H),3.29–3.47 (2H), 3.64–4.04 (4H), 4.12–4.35 (2H), 4.41+4.51 (1H), 5.20(1H), 6.59 (1H), 7.09 (1H), 7.23 (1H), 7.63 (1H), 8.60 (1H) ppm.

Production of(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane;Variant II: Example 1i(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[Diphenyl(1,1-dimethylethyl)silyl]oxy]-5-hydroxy-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(4-(trimethylsilyl)-but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10E/Z,13S,14E))-4-(13-[[diphenyl(1,1-dimethylethyl)silyl]oxy]-5-hydroxy-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(4-(trimethylsilyl)-but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1c, 2.85 g (8.78 mmol) of the compound, producedaccording to Example 1b, is reacted with 3.62 g (6.71 mmol) of(2S,6E/Z,9S,10E)-2,6,10-trimethyl-9-[[diphenyl(1,1-dimethylethyl)silyl]oxy]-1-oxo-1-(2-pyridyl)-undeca-6,10-diene,which was produced analogously to the process that is described in DE197 51 200.3, and after working-up and purification, in addition tostarting material, 1.28 g (1.48 mmol, 22%) of title compound C as wellas 1.73 g (2.00 mmol, 30%) of title compound B are isolated in each caseas a colorless oil.

¹H-NMR (CDCl₃) of A: δ=0.13 (9H), 0.86–2.52 (36H), 1.08 (9H), 1.42+1.58(3H), 2.01 (3H), 3.32–4.85 (9H), 5.00 (1H), 6.23 (1H), 6.97–7.09 (2H),7.21–7.45 (6H), 7.57 (1H), 7.61–7.75 (4H), 8.56 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.12 (9H), 0.77–2.53 (36H), 1.08 (9H), 1.38+1.62(3H), 2.00 (3H), 3.23–4.86 (9H), 5.02 (1H), 6.23 (1H), 6.96–7.09 (2H),7.19–7.47 (6H), 7.53–7.76 (5H), 8.57 (1H) ppm.

Example 1j(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[Diphenyl(1,1-dimethylethyl)silyl]oxy]-5-(tetrahydro-2H-pyran-2-yloxy)-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(4-(trimethylsilyl)-but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1d, 1.16 g (1.34 mmol) of the compound that isproduced according to Example 1i is reacted, and after working-up andpurification, 1.12 g (1.18 mmol, 88%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.13 (9H), 0.86–2.52 (39H), 1.08 (9H), 2.01 (3H),3.32–4.85 (9H), 5.00 (1H), 6.22 (1H), 6.96–7.09 (2H), 7.21–7.44 (6H),7.56 (1H), 7.61–7.75 (4H), 8.56 (1H) ppm.

Example 1h Variant II(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-Hydroxy-5-(tetrahydro-2H)-pyran-2-yloxy)-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(but-3-in-1-yl)-undec-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1e, 1.12 g (1.18 mmol) of the compound that isproduced according to Example 1j is reacted, and after working-up andpurification, 654 mg (1.03 mmol, 87%) of the title compound is isolatedas a colorless oil. The coverage of the ¹H-NMR spectrum is identical tothat described in Example 1h, Variant I.

Example 1k(3S,6R,7S,8S,12E/Z,15S,16E)-1,3,7,15-Tetrahydroxy-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dien-5-one

The solution of 654 mg (1.03 mmol) of the compound, produced accordingto Example 1h, in 27 ml of anhydrous ethanol is mixed under anatmosphere of dry argon with 588 mg of p-toluenesulfonicacid-monohydrate, and it is stirred for 3 hours at 23° C. After removalof the solvent, the residue is chromatographed on fine silica gel with amixture of n-hexane and ethyl acetate. 484 mg (942 μmol, 91%) of thetitle compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.90+0.92 (3H), 1.07 (3H), 1.11–2.16 (14H), 1.29 (3H),1.63+1.42 (3H), 2.00+2.02 (3H), 2.20–2.60 (4H), 2.98 (1H), 3.48–3.67(2H), 3.78–3.93 (2H), 4.06–4.23 (3H), 5.16+5.24 (1H), 6.52+6.57 (1H),7.11 (1H), 7.30 (1H), 7.66 (1H), 8.58 (1H) ppm.

Example 1l(3S,6R,7S,8S,12E/Z,15S,16E)-1,3,7,15-Tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dien-5-one

The solution of 673 mg (1.31 mmol) of the compound, produced accordingto Example 1k, in 37 ml of anhydrous dichloromethane is cooled under anatmosphere of dry argon to −78° C., mixed with 2.14 ml of 2,6-lutidine,2.41 ml of trifluoromethanesulfonic acid-tert-butyldimethylsilylester,allowed to heat within 2 hours to 0° C. and stirred for another 2 hours.It is poured into saturated sodium bicarbonate solution and extractedseveral times with dichloromethane. The combined organic extracts aredried on sodium sulfate and concentrated by evaporation in a vacuum.After column chromatography on silica gel with a gradient system thatconsists of n-hexane and ethyl acetate, 1.11 g (1.29 mmol, 99%) of thetitle compound is isolated as a colorless oil.

¹H-NMR (CDCl₃) δ=−0.01–0.12 (24H), 0.82–2.33 (55H), 1.08 (3H), 1.22(3H), 1.60+1.68 (3H), 2.05 (3H), 3.22 (1H), 3.51–3.73 (2H), 3.81 (1H),3.92 (1H), 4.11 (1H), 5.18 (1H), 6.47 (1H) 7.08 (1H), 7.22 (1H), 7.61(1H), 8.59 (1H) ppm.

Example 1m(3S,6R,7S,8S,12E/Z,15S,16E)-1-Hydroxy-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dien-5-one

The solution of 1.10 mg (1.13 mmol) of the compound, produced accordingto Example 1l, in a mixture of 14 ml of dichloromethane and 14 ml ofmethanol is mixed at 23° C. under an atmosphere of dry argon with 312 mgof campher-10-sulfonic acid, and it is stirred for 2 hours. It is pouredinto a saturated sodium bicarbonate solution and extracted several timeswith dichloromethane. The combined organic extracts are dried on sodiumsulfate and concentrated by evaporation in a vacuum. After columnchromatography on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate, 814 mg (950 pmol, 84%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.01–0.13 (18H), 0.83–2.33 (47H), 1.12 (3H), 1.23(3H), 1.61+1.68 (3H), 2.05 (3H), 3.28 (1H), 3.68 (2H), 3.84 (1H),4.02–4.18 (2H), 5.18 (1H), 6.48 (1H), 7.08 (1H), 7.22 (1H), 7.61 (1H),8.60 (1H) ppm.

Example 1n(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dienal

The solution of 0.129 ml of oxalyl chloride in 6.3 ml of anhydrousdichloromethane is cooled under an atmosphere of dry argon to −70° C.,mixed with 209 μl of dimethyl sulfoxide, the solution of 814 mg (950μmol) of the compound, produced according to Example 1m, in 6.3 ml ofanhydrous dichloromethane, and it is stirred for 0.5 hour. Then, it ismixed with 646 μl of triethylamine, allowed to react for 1 hour at −30°C. and mixed with n-hexane and saturated sodium bicarbonate solution.The organic phase is separated, the aqueous phase is extracted severalmore times with n-hexane, the combined organic extracts are washed withwater and dried on magnesium sulfate. The residue that is obtained afterfiltration and removal of the solvent is further reacted withoutpurification.

Example 1o(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12E,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dienoicacid (B)

The solution of 852 mg (max. 950 μmol) of the compound, producedaccording to Example in, in 23 ml of acetone is cooled to −30° C., mixedwith 1.19 ml of a standardized, 8N chromosulfuric acid solution andstirred for 1 hour. It is poured into a mixture that consists of waterand diethyl ether, the organic phase is washed with saturated sodiumchloride solution and dried on sodium sulfate. After filtration andremoval of the solvent, the residue is purified by chromatography on afine silica gel with a gradient system that consists of n-hexane andethyl acetate. 298 mg (342 mol, 36% relative to the educt in Example 11)of title compound A as well as 234 mg (269 μmol, 28% relative to theeduct in Example 11) of title compound B are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.02–0.15 (18H), 0.81–0.99 (30H), 1.05–2.3(15H), 1.12 (3H), 1.24 (3H), 1.71 (3H), 1.92 (3H), 2.38 (1H), 2.51 (1H),3.27 (1H), 3.80 (1H), 4.17 (1H), 4.43 (1H), 5.23 (1H), 6.67 (1H), 7.18(1H), 7.36 (1H), 7.72 (1H), 8.62 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.01–0.19 (18H), 0.80–0.96 (30H), 1.00–2.45(16H), 1.13 (3H), 1.27 (3H), 1.57 (3H), 1.94 (3H), 2.54 (1H), 3.28 (1H),3.88 (1H), 4.13 (1H), 4.40 (1H), 5.12 (1H), 6.49 (1H), 7.18 (1H), 7.38(1H), 7.71 (1H), 8.62 (1H) ppm.

Example 1p(3S,6R,7S,8S,12Z,15S,16E)-15-Hydroxy-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 298 mg (342 μmol) of compound A, producedaccording to Example 1o, is reacted, and after working-up, 294 mg (max.342 μmol) of the title compound is isolated as a crude product, which isfurther reacted without purification.

Example 1q(4S,7R,8S,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione

The solution of 294 mg (max. 342 μmol) of the compound, producedaccording to Example 1p, in a mixture that consists of 2.6 ml ofanhydrous tetrahydrofuran and 30 ml of toluene is mixed under anatmosphere of dry argon with 284 μl of triethylamine, 268 μl of2,4,6-trichlorobenzoyl chloride, and it is stirred for 20 minutes. Thissolution is added in drops within 4.5 hours to the solution of 434 mg of4-dimethylaminopyridine in 132 ml of toluene, and it is stirred for 0.5more hour at 23° C. It is concentrated by evaporation, taken up in alittle dichloromethane and purified by chromatography on fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 136mg (184 μmol, 54%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): =−0.08 (3H), 0.13 (9H), 0.80–2.32 (12H), 0.85 (9H), 0.94(9H), 0.99 (3H), 1.15 (3H), 1.24 (3H), 1.68 (3H), 2.13 (3H), 2.47 (1H),2.59–2.89 (3H), 3.11 (1H), 4.00 (1H), 4.06 (1H), 5.00 (1H), 5.18 (1H),6.57 (1H), 7.10 (1H), 7.26 (1H), 7.63 (1H), 8.60 (1H) ppm.

Example 1r(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione

The solution of 20 mg (27 μmol) of the compound, produced according toExample 1p, in 2 ml of anhydrous tetrahydrofuran is mixed under anatmosphere of dry argon in portions with a total of 0.57 ml ofHF-pyridine complex, and it is stirred at 23° C. for 24 hours. It ispoured into saturated sodium bicarbonate solution, extracted severaltimes with dichloromethane, and the combined organic extracts are driedon sodium sulfate. After filtration and removal of the solvent, theresidue that is obtained is purified by chromatography on fine silicagel with a mixture that consists of n-hexane and ethyl acetate. 9.1 mg(17.9 μmol, 66%) of the title compound is isolated as a colorless oil aswell as mg of monosilylether.

¹H-NMR (CDCl₃)=1.09 (6H), 1.19–2.12 (11H), 1.38 (3H), 6.9 (3H), 2.06(3H), 2.21–2.41 (3H), 2.50 (1H), 2.63 (1H), 2.68 (1H), 3.53 (1H), 3.70(1H), 4.42 (1H), 4.59 (1H), 5.12 (1H), 5.22 (1H), 6.61 (1H), 7.13 (1H),7.29 (1H), 7.68 (1H), 8.53 (1H) ppm.

Example 2(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 2a(4S,7R,8S,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione

The solution of 25 mg (34 μmol) of the compound, produced according toExample 1q, in 3 ml of ethanol, is mixed with 25 μl of pyridine, acatalytic amount of palladium on barium sulfate (10%), and it ishydrogenated under 1 atmosphere of hydrogen. After filtration andremoval of the solvent, the residue is purified by chromatography on ananalytical thin-layer plate. As a mobile solvent, a mixture of n-hexaneand ethyl acetate is used. 13 mg (18 μmol, 52%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.10 (3H), 0.06 (3H), 0.11 (6H), 0.80–2.20 (1H), 0.83(9H), 0.92 (9H), 0.98 (3H), 1.12 (3H), 1.19 (3H), 1.67 (3H), 2.12 (3H),2.43 (1H), 2.55–2.82 (3H), 3.07 (1H), 4.00 (1H), 4.03 (1H), 4.90–5.03(3H), 5.18 (1H), 5.72 (1H), 6.57 (1H), 7.09 (1H), 7.25 (1H), 7.62 (1H),8.59 (1H) ppm.

Example 2b(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 10.3 mg (14 μmol) of the compound that isproduced according to Example 2a is reacted, and after working-up andpurification, 5.7 mg (11 μmol, 80%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=1.04 (3H), 1.09 (3H), 0.25–2.38 (13H), 1.36 (3H), 1.70(3H), 2.07 (3H), 2.48 (1H), 2.63 (1H), 2.74 (1H), 3.31 (1H), 3.69 (1H),4.38 (1H), 4.61 (1H), 4.97 (1H), 5.02 (1H), 5.11 (1H), 5.19 (1H), 5.77(1H), 6.60 (1H), 7.13 (1H), 7.29 (1H), 7.68 (1H), 8.54 (1H) ppm.

Example 3(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 3a(3S,6R,7S,8S,12E,15S,16E)-15-Hydroxy-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(but-3-in-1-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 234 mg (269 μmol) of compound B that isproduced according to Example 1o is reacted, and after working-up, 229mg (max. 269 μmol) of the title compound is isolated as a crude product,which is further reacted without purification.

Example 3b(4S,7R,8S,9S,13E,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 229 mg (max. 269 μmol) of the compound thatis produced according to Example 3a is reacted, and after working-up andpurification, 112 mg (152 μmol, 56%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.05 (3H), 0.11 (6H), 0.15 (3H), 0.80–2.30 (33H), 1.13(3H), 1.21 (3H), 1.62 (3H), 2.61 (3H), 2.40–2.72 (4H), 3.10 (1H), 3.91(1H), 4.46 (1H), 5.22 (1H), 5.30 (1H), 6.56 (1H), 7.09 (1H), 7.20 (1H),7.62 (1H), 8.60 (1H) ppm.

Example 3c(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 72 mg (98 μmol) of the compound that isproduced according to Example 3b is reacted, and after working-up andpurification, 32 mg (63 μmol, 64%) of the title compound is isolated asa colorless foam.

¹H-NMR (CDCl₃): δ=1.00 (3H), 1.04 (3H), 1.30–2.71 (16H), 1.32 (3H), 1.61(3H), 2.10 (3H), 3.63 (1H), 3.70 (1H), 3.86 (1H), 3.99 (1H), 4.48 (1H),5.10 (1H), 5.41 (1H), 6.58 (1H), 7.13 (1H), 7.33 (1H), 7.68 (1H), 8.54(1H) ppm.

Example 4(1S,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

The solution of 5 mg (10 μmol) of the compound, produced according toExample 1, in 1 ml of dichloromethane is mixed under an atmosphere ofdry argon at −20° C. with 11.3 μl of a 20% solution of trifluoroaceticacid in dichloromethane and 5.6 mg of m-chloroperbenzoic acid (60%). Itis stirred for 18 hours at −18° C., poured onto saturated sodiumthiosulfate solution, extracted several times with dichloromethane, thecombined organic extracts are washed with sodium bicarbonate solution,saturated sodium chloride solution and dried on magnesium sulfate. Theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on an analytical thin-layer plate. As amobile solvent and eluant, a mixture that consists of dichloromethaneand ethanol is used. 1.3 mg (2.5 μmol, 25%) of title compound A (or B)and 2.0 mg (3.8 μmol, 39%) of title compound B (or A) are isolated ineach case as a colorless oil.

¹H-NMR (CDCl₃) of A (or B): δ=1.01 (3H), 1.07 (3H), 1.23–2.20 (13H),1.30 (3H), 1.46 (3H), 2.10 (3H), 2.26 (1H), 2.40 (1H), 2.58 (1H), 2.82(1H), 2.97 (1H), 3.63 (2H), 4.39 (1H), 5.22 (1H), 5.47 (1H), 6.61 (1H),7.15 (1H), 7.28 (1H), 7.69 (1H), 8.55 (1H) ppm.

¹H-NMR (CDCl₃) of B (or A): δ=0.98 (3H), 1.08 (3H), 1.27–2.19 (13H),1.32 (3H), 1.43 (3H), 2.12 (3H), 2.30 (1H), 2.48 (1H), 2.70 (1H), 2.96(1H), 3.15 (1H), 3.4.7 (1H), 3.57 (1H), 4.01 (1H), 4.49 (1H), 5.50 (1H),6.67 (1H), 7.12 (1H), 7.27 (1H), 7.66 (1H), 8.58 (1H) ppm.

Example 5(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 4, 6.6 mg (13 μmol) of the compound that isproduced according to Example 2 is reacted, and after working-up andpurification, 1.4 mg (2.7 μmol, 20%) of title compound A (or B) and 0.9mg (1.7 μmol, 13%) of title compound B (or A) are isolated in each caseas a colorless foam.

¹H-NMR (CDCl₃) of A (or B): δ=1.00 (3H), 1.07 (3H), 1.21–2.05 (12H),1.30 (3H), 1.40 (3H), 2.10 (3H), 2.16 (1H), 2.38 (1H), 2.57 (1H), 2.81(1H), 2.97 (1H), 3.44 (1H), 3.63 (1H), 4.38 (1H), 4.98 (1H), 5.02 (1H),5.28 (1H), 5.45 (1H), 5.77 (1H), 6.62 (1H), 7.18 (1H), 7.31 (1H), 7.71(1H), 8.56 (1H) ppm.

¹H-NMR (CDCl₃) of B (or A): δ=0.94 (3H), 1.05 (3H), 1.18–2.17 (13H),1.30 (3H), 1.38 (3H), 2.12 (3H), 2.48 (1H), 2.62 (1H), 2.95 (1H), 3.28(1H), 3.30 (1H), 3.50 (1H), 3.96 (1H), 4.41 (1H), 4.95 (1H), 5.00 (1H),5.52 (1H), 5.25 (1H), 6.73 (1H), 7.18 (1H), 7.33 (1H), 7.71 (1H), 8.58(1H) ppm.

Example 6(1S,3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 4, 14 mg (27 μmol) of the compound that isproduced according to Example 3 is reacted, and after working-up andpurification, 7.8 mg (15 mol, 55%) of title compound A (or B) and 4.7 mg(9 μmol, 33%) of title compound B (or A) are isolated in each case as acolorless foam.

¹H-NMR (CDCl₃) of A (or B): δ=0.93 (3H), 1.04 (3H), 1.23–2.19 (13H),1.29 (3H), 1.42 (3H), 2.13 (3H), 2.28 (1H), 2.48–2.65 (2H), 2.71 (1H),2.89 (1H), 3.57 (1H), 3.83 (1H), 4.36 (1H), 4.47 (1H), 5.51 (1H), 6.63(1H), 7.12 (1H), 7.28 (1H), 7.67 (1H), 8.57 (1H) ppm.

¹H-NMR (CDCl₃) of B (or A): δ=0.96 (3H), 1.10 (3H), 1.21–2.18 (13H),1.26 (3H), 1.40 (3H), 2.10 (3H), 2.29 (1H), 2.61 (2H), 2.86 (1H), 2.99(1H), 3.58 (1H), 3.79 (2H), 4.37 (1H), 5.46 (1H), 6.61 (1H), 7.12 (1H),7.26 (1H), 7.66 (1H), 8.57 (1H) ppm.

Example 7(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 2a, 14 mg (27 μmol) of the compound that isproduced according to Example 3 is reacted, and after working-up andpurification, 4.1 mg (8 μmol, 29%) of the title compound is isolated asa colorless foam.

¹H-NMR (CDCl₃): δ=0.98 (3H), 1.02 (3H), 1.30 (3H), 1.36–2.68 (16H), 1.61(3H), 2.09 (3H), 3.43 (1H), 3.70 (1H), 4.17 (1H), 4.45 (1H), 4.94 (1H),5.00 (1H), 5.09 (1H), 5.39 (1H), 5.72 (1H), 6.58 (1H), 7.12 (1H), 7.35(1H), 7.67 (1H), 8.52 (1H) ppm.

Example 8(1S,3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 4, 4.1 mg (8 μmol) of the compound that isproduced according to Example 7 is reacted, and after working-up andpurification, 1.7 mg (3.2 μmol, 40%) of title compound A (or B) and 0.4mg (0.8 μmol, 9%) of title compound B (or A) are isolated in each caseas a colorless foam.

¹H-NMR (CDCl₃) of A (or B): δ=0.91 (3H), 1.02 (3H), 1.13–2.17 (15H),1.28 (3H), 1.38 (3H), 2.11 (3H), 2.53 (2H), 2.87 (1H), 2.96 (1H), 3.38(1H), 3.78 (1H), 4.35 (1H), 4.37 (1H), 4.95 (1H), 5.00 (1H), 5.50 (1H),5.76 (1H), 6.64 (1H), 7.12 (1H), 7.30 (1H), 7.67 (1H), 8.57 (1H) ppm.

¹H-NMR (CDCl₃) of B (or A): δ=0.92 (3H), 1.09 (3H), 1.18–2.13 (15H),1.26 (3H), 1.38 (3H), 2.08 (3H), 2.49–2.60 (2H), 2.85–2.99 (2H), 3.39(1H), 3.72 (1H), 3.89 (1H), 4.28 (1H), 4.92–5.06 (2H), 5.45 (1H), 5.76(1H), 6.60 (1H), 7.12 (1H), 7.26 (1H), 7.68 (1H), 8.57 (1H) ppm.

Example 9(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 9a(3RS,4S)-4-(2-Methyl-3-hydroxy-hept-6-en-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1a, 5.5 g (30 mmol) of(4S)-4-(2-methyl-1-oxo-prop-2-yl)-2,2-dimethyl-[1,3]dioxane, which wasproduced analogously to the process described in DE 197 51 200.3, isreacted with but-3-en-1-yl-magnesium bromide, and after working-up andpurification, 3.84 g (15.8 mmol, 53%) of the title compound is isolatedas a colorless oil.

Example 9b(4S)-4-(2-Methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1b, 3.84 g (15.8 mmol) of the compound that isproduced according to Example 9a is reacted, and after working-up andpurification, 3.0 g (12.5 mmol, 79%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.07 (3H), 1.14 (3H), 1.33 (4H), 1.41 (3H), 1.62 (1H),2.29 (2H), 2.60 (2H), 3.86 (1H), 3.97 (1H), 4.05 (1H), 4.96 (1H), 5.02(1H), 5.81 (1H) ppm.

Example 9c(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-5-hydroxy-2,6,10,14-tetramethyl-3-oxo-15-(2-methylthiazol-4-yl)-4-(prop-2-en-1-yl)-pentadec-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10E/Z,13S,14E))-4-(13-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-hydroxy-2,6,10,14-tetramethyl-3-oxo-15-(2-methylthiazol-4-yl)-4-(prop-2-en-1-yl)-pentadec-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1c, 2.07 g (8.61 mmol) of the compound, producedaccording to Example 9b, with 2.01 g (4.61 mmol) of(2S,6E/Z,9S,10E)-2,6,10-trimethyl-9-[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-oxo-11-(2-methylthiazol-4-yl)-undeca-6,10-dienethat was produced analogously to the process that is described in DE 19751 200.3 is reacted, and after working-up and purification, in additionto starting material, 995 mg (1.47 mmol, 32%) of title compound A aswell as 784 mg (1.16 mmol, 25%) of title compound B are isolated in eachcase as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=0.01 (3H), 0.07 (3H), 0.85 (3H), 0.90 (9H), 0.98(3H), 1.00–2.33 (12H), 1.23 (3H), 1.33 (3H), 1.39 (3H), 1.60+1.67 (3H),2.00 (3H), 2.46 (1H), 2.72 (3H), 2.99 (1H), 3.34 (1H), 3.49 (1H), 3.87(1H), 3.98 (1H), 4.09 (1H), 4.13 (1H), 4.98 (1H), 5.03 (1H), 5.13 (1H),5.71 (1H), 6.44 (1H), 6.93 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.00 (3H), 0.03 (3H), 0.88 (9H), 0.94 (3H),1.03–1.72 (7H), 1.08 (3H), 1.17 (3H), 1.31 (3H), 1.39 (3H), 1.60+1.68(3H), 1.89–2.08 (2H), 1.99 (3H), 2.17–2.51 (4H), 2.71 (3H), 2.74+2.87(1H), 3.31 (1H), 3.57 (1H), 3.84 (1H), 3.95 (1H), 4.03–4.17 (2H), 4.98(1H), 5.03 (1H), 5.13 (1H), 5.73 (1H), 6.64 (1H), 6.92 (1H) ppm.

Example 9d(3S,6R,7S,8S,12E/Z,15S,16E)-15-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-1,3,7-trihydroxy-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-6-(prop-2-en-1-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1k, 1.33 g (1.97 mmol) of compound A that isproduced according to Example 9c is reacted, and after working-up andpurification, 1.02 g (1.60 mmol, 81%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.07 (3H), 0.89 (12H), 1.00–2.38 (12H),1.40+1.07 (3H), 1.23+1.25 (3H), 1.60+1.68 (3H), 1.97+1.99 (3H), 2.52(1H), 2.67–2.89 (1H), 2.73+2.77 (3H), 3.01 (1H), 3.33 (1H), 3.40–3.53(1H), 3.74–3.9.3 (3H), 4.03–4.19 (2H), 5.00 (1H), 5.06 (1H), 5.10+5.20(1H), 5.71 (1H), 6.42 (1H), 6.93 (1H) ppm.

Example 9e(3S,6R,7S,8S,12E/Z,15S,16E)-1,3,7,15-Tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy[4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-6-(prop-2-en-1-yl)-heptadeca-1,2,16-dien-5-one

Analogously to Example 11, 1.02 g (1.60 mmol) of the compound that isproduced according to Example 9d is reacted, and after working-up andpurification, 1.46 g (1.49 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.11 (24H), 0.83–0.98 (39H), 1.01–1.62 (8H), 1.07(3H), 1.20 (3H), 1.59+1.67 (3H), 1.97 (1H), 2.00 (3H), 2.19–2.34 (3H),2.48 (1H), 2.72 (3H); 3.13 (1H), 3.57 (1H), 3.67 (1H), 3.78 (1H), 3.87(1H), 4.09 (1H), 4.93 (1H), 4.99 (1H), 5.15 (1H), 5.77 (1H), 6.64 (1H),6.91 (1H) ppm.

Example 9f(3S,6R,7S,8S,12E/Z,15S,16E)-1-Hydroxy-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-6-(prop-2-en-1-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1m, 1.45 g (1.48 mmol) of the compound that isproduced according to Example 9e is reacted, and after working-up andpurification, 1.19 g (1.37 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.01–0.14 (18H), 0.82–0.97 (30H), 1.04–1.70 (7H), 1.09(3H), 1.19 (3H), 1.59+1.68 (3H), 1.84–2.08 (3H), 2.00 (3H), 2.18–2.36(3H), 2.47 (1H), 2.71 (3H), 3.13 (1H), 3.66 (2H), 3.80 (1H), 4.40 (1H),4.10 (1H), 4.96 (1H), 5.01 (1H), 5.14 (1H), 5.77 (1H), 6.46 (1H), 6.92(1H) ppm.

Example 9g(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[(dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-5-oxo-6-(prop-2-en-1-yl)-heptadeca-12,16-dienal

Analogously to Example in, 1.18 g (1.37 mmol) of the compound that isproduced according to Example 9f is reacted, and after working-up, 1.25g (max. 1.37 mmol) of the title compound is isolated as a yellow oil,which is further reacted without purification.

Example 9h(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-5-oxo-6-(prop-2-en-1-yl)-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12E,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-5-oxo-6-(prop-2-en-1-yl)-heptadeca-12,16-dienoicacid (B)

Analogously to Example 1o, 1.25 g (max. 1.37 mmol) of the compound thatis produced according to Example 9g is reacted, and after working-up andpurification, 302 mg (0.34 mmol, 25%) of title compound A and 230 mg(0.26 mmol, 19%) of title compound B are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.02–0.15 (18H), 0.82–0.97 (30H), 1.05–2.53(14H), 1.12 (3H), 1.17 (3H), 1.70 (3H), 1.96 (3H), 2.71 (3H), 3.17 (1H),3.72 (1H), 4.16 (1H), 4.37 (1H), 4.94 (1H), 4.99 (1H), 5.20 (1H), 5.73(1H), 6.66 (1H), 6.93 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.03–0.15 (18H), 0.81–0.95 (30H), 1.01–2.50(13H), 1.12 (3H), 1.18 (3H), 1.57 (3H), 1.95 (3H), 2.60 (1H), 2.70 (3H),3.22 (1H), 3.79 (1H), 4.08 (1H), 4.32 (1H), 4.94 (1H), 5.00 (1H), 5.11(1H) 5.74 (1H), 6.46 (1H), 6.93 (1H) ppm.

Example 9i(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-15-hydroxy-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-5-oxo-6-(prop-2-en-1-yl)-heptadecane-12,16-dienoicacid

Analogously to Example 1e, 302 mg (0.34 mmol) of compound A that isproduced according to Example 9h is reacted, and after working-up, 296mg (max. 0.34 mmol) of the title compound is isolated as a pale yellowoil, which is further reacted without purification.

Example 9j(4S,7R,8S,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-methylthiazol-4-yl)-ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 296 mg (max. 0.34 mmol) of the compound thatis produced according to Example 9i is reacted, and after working-up andpurification, 166 mg (0.22 mmol, 65%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.10 (3H), 0.09 (3H), 0.11 (3H), 0.13 (3H), 0.86(9H), 0.80–2.85 (13H), 0.94 (9H), 1.00 (3H), 1.10 (3H), 12.0 (3H), 1.68(3H), 2.10 (3H), 2.71 (3H), 3.11 (1H), 4.01 (2H), 4.85–5.03 (3H), 5.16(1H), 5.78 (1H), 6.57 (1H), 6.98 (1H) ppm.

Example 9k(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 25 mg (34 μmol) of the compound that isproduced according to Example 9j is reacted, and after working-up andpurification, 10 mg (19 μmol, 57%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=1.03 (3H), 1.05 (3H), 1.20–2.74 (14H), 1.30 (3H), 1.69(3H), 2.07 (3H), 2.69 (3H), 3.33 (1H), 3.69 (1H), 3.72 (1H), 4.23 (1H),5.02 (1H), 5.07 (1H), 5.12 (1H), 5.21 (1H), 5.76 (1H), 6.57 (1H), 6.96(1H) ppm.

Example 10(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

The solution of 8.0 mg (15.5 μmol) of the compound, produced accordingto Example 9, in 1 ml of acetonitrile is mixed with 89 μl of a 1Msolution of sodium ethylenediamine tetraacetate, cooled to 0° C. andmixed with 148 μl of 1,1,1-trifluoroacetone as well as a mixture thatconsists of 22 mg of oxone and 41 mg of sodium bicarbonate. It isallowed to react for 5 hours, poured onto sodium thiosulfate solutionand extracted several times with ethyl acetate. The combined organicextracts are washed with saturated sodium chloride solution, and theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on an analytic thin-layer plate. As a mobilesolvent, a mixture of n-hexane and ethyl acetate is used. 3.2 mg (6μmol, 39%) of title compound A and 1.0 mg (2 μmol, 12%) of titlecompound B are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=1.00 (3H), 1.02 (3H), 1.21–1.82 (7H), 1.29 (3H),1.36 (3H), 1.95–2.06 (2H), 2.11 (3H), 2.30 (1H), 2.40 (1H), 2.48–2.62(2H), 2.72 (3H), 2.81 (2H), 3.50 (1H), 3.69 (1H), 4.27 (1H), 4.52 (1H),5.01 (1H), 5.06 (1H), 5.46 (1H), 5.72 (1H), 6.59 (1H), 6.99 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.96 (3H), 1.00 (3H), 1.20–1.91 (8H), 1.29 (3H),1.34 (3H), 2.04 (1H), 2.09 (3H), 2.33 (1H), 2.42–2.61 (3H), 2.76 (3H),2.93 (1H), 2.96 (1H), 3.38 (1H), 3.68 (1H), 3.99 (1H), 4.29 (1H), 4.98(1H), 5.01 (1H), 5.57 (1H), 5.74 (1H), 6.69 (1H), 7.01 (1H) ppm.

Example 11(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 11a(3S,6R,7S,8S,12E,15S,16E)-3,7-Bis-[(dimethyl(1,1-dimethylethyl)silyl]oxy]-15-hydroxy-4,4,8,12,16-pentamethyl-17-(2-methylthiazol-4-yl)-5-oxo-6-(prop-2-en-1-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 230 mg (0.26 mmol) of compound B that isproduced according to Example 9h is reacted, and after working-up, 214mg (max. 0.26 mmol) of the title compound is isolated as a pale yellowoil, which is further reacted without purification.

Example 11b(4S,7R,8S,9S,13E,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 214 mg (max. 0.26 mmol) of the compound thatis produced according to Example 11a is reacted, and after working-upand purification, 114 mg (0.15 mmol, 59%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.05 (3H), 0.08 (3H), 0.10 (3H), 0.13 (3H), 0.82–0.94(21H), 1.12 (3H), 1.15–2.62 (13H), 1.21 (3H), 1.59 (3H), 2.11 (3H), 2.71(3H), 3.03 (1H), 3.87 (1H), 4.30 (1H), 4.99 (1H), 5.03 (1H), 5.21 (1H),5.28 (1H), 5.79 (1H), 6.51 (1H), 6.91 (1H) ppm.

Example 11c(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 15 mg (20 μmol) of the compound that isproduced according to Example 11b is reacted, and after working-up andpurification, 7.3 mg (14 μmol, 71%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.80–2.62 (13H), 0.99 (3H), 1.01 (3H), 1.26 (3H), 1.60(3H), 2.04 (3H), 2.69 (3H), 3.49 (1H), 3.73 (1H), 4.01 (1H), 4.12 (1H),4.42 (1H), 4.95–5.10 (3H), 5.37 (1H), 5.71 (1H), 6.56 (1H), 6.99 (1H)ppm.

Example 12(1R,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 10, 7.3 mg (14 μmol) of the compound that isproduced according to Example 11 is reacted, and after working-up andpurification, 2.3 mg (4.3 μmol, 31%) of title compound A (or B) and 2.0mg (3.7 μmol, 27%) of title compound B (or A) are isolated in each caseas a colorless oil.

¹H-NMR (CDCl₃) of A (or B): δ=0.90–2.34 (10H), 0.95 (3H), 1.01 (3H),1.29 (3H), 1.38 (3H), 2.10 (3H), 2.47–2.62 (3H), 2.72 (3H), 2.88 (2H),3.48 (1H), 3.80 (1H), 4.19 (1H), 4.32 (1H), 5.02 (1H), 5.07 (1H), 5.48(1H), 5.77 (1H), 6.63 (1H), 7.00 (1H) ppm.

¹H-NMR (CDCl₃) of B (or A): δ=0.97 (3H), 1.06 (3H), 1.20–2.12 (9H), 1.25(3H), 1.34 (3H), 2.08 (3H), 2.28 (1H), 2.46–2.62 (3H), 2.72 (3H), 2.92(2H), 3.40 (1H), 3.68 (1H), 3.75 (1H), 4.28 (1H), 5.01 (1H), 5.06 (1H),5.44 (1H), 5.72 (1H), 6.62 (1H), 6.99 (1H) ppm.

Example 13(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 13a(3RS,4S)-4-(2-Methyl-3-hydroxy-8-(trimethylsilyl)-hept-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1a, 7.0 g (37 mmol) of(4S)-4-(2-methyl-1-oxo-prop-2-yl)-2,2-dimethyl-[1,3]dioxane, which wasproduced analogously to the process described in DE 197 51 200.3, isreacted with 4-trimethylsilyl-but-3-in-1-yl-magnesium bromide, and afterworking-up and purification, 4.9 g (15.7 mmol, 42%) of the titlecompound is isolated as a colorless oil.

Example 13b(4S)-4-(2-Methyl-3-oxo-8-(trimethylsilyl)-hept-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1b, 4.87 g (15.6 mmol) of the compound that isproduced according to Example 13a is reacted, and after working-up andpurification, 4.10 g (13.2 mmol, 85%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.13 (9H), 1.08 (3H), 1.13 (3H), 1.32 (1H), 1.34 (3H),1.41 (3H), 1.61 (1H), 2.45 (2H), 2.73 (2H), 3.84 (1H), 3.96 (1H), 4.02(1H) ppm.

Example 13c(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-5-hydroxy-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(4-(trimethylsilyl)-prop-2-in-1-yl)-pentadec-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and (4S(4S,5R,6S,10E/Z,13S,14E))-4-(13-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-hydroxy-2,6,10,14-tetramethyl-3-oxo-15-(2-pyridyl)-4-(4-(trimethylsilyl)-prop-2-in-1-yl)-pentadec-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1c, 2.74 g (8.82 mmol) of the compound that isproduced according to Example 13b is reacted with 3.02 g (7.27 mmol) of(2S,6E/Z,9S,10E)-2,6,10-trimethyl-9-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-oxo-11-(2-pyridyl)-undeca-6,10-diene,which was produced analogously to the process that is described in DE197 51 200.3, and after working-up and purification, in addition to 50%starting material, 1.63 g (2.2 mmol, 31%) of title compound A and 0.50 g(0.69 mmol, 9%) of title compound B are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=0.00–0.20 (15H), 0.83–0.95 (12H), 1.00–1.80(20H), 1.60+1.68 (3H), 1.90–2.10 (1H), 2.05 (3H), 2.28 (2H), 2.41 (1H),2.55 (1H), 3.03+3.09 (1H), 3.46 (1H), 3.52 (1H), 3.78–4.20 (4H), 5.18(1H), 6.49 (1H), 7.09 (1H), 7.23 (1H), 7.63 (1H), 8.60 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.00–0.20 (15H), 0.86–1.00 (12H), 1.00–1.76(19H), 1.61+1.70 (3H), 1.90–2.10 (2H), 2.06 (3H), 2.29 (2H), 2.53 (2H),3.04 (1H), 3.43 (1H), 3.61 (1H), 3.80–4.18 (4H), 5.18 (1H), 6.48 (1H),7.09 (1H), 7.23 (1H), 7.62 (1H), 8.59 (1H) ppm.

Example 13d(3S,6R,7S,8S,12E/Z,15S,16E)-15-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-1,3,7-trihydroxy-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1k, 2.25 g (3.10 mmol) of the compound that isproduced according to Example 13c is reacted, and after working-up andpurification, in addition to starting material, 1.31 g (1.91 mmol, 62%)of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.19 (9H), 0.85–0.98 (12H), 1.03–2.43 (25H),1.60+1.69 (3H), 2.00+2.02 (3H), 2.69 (1H), 3.01+3.10 (1H), 3.31–3.60(3H), 3.84 (2H), 4.02–4.26 (2H), 5.10+5.26 (1H), 6.41 (1H), 7.13 (1H),7.32 (1H), 7.68 (1H), 8.61 (1H) ppm.

Example 13e(3S,6R,7S,8S,12E/Z,15S,16E)-1,3,7,15-Tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 11, 1.49 g (2.17 mmol) of the compound that isproduced according to Example 13d is reacted, and after working-up andpurification, 1.95 g (1.90 mmol, 87%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.18 (33H), 0.86–0.98 (39H), 1.01–1.73 (7H), 1.08(3H), 1.26 (3H), 1.61+1.69 (3H), 1.90–2.09 (2H), 2.05 (3H), 2.29 (2H),2.51 (2H), 3.29 (1H), 3.53–3.71 (2H), 3.79 (1H), 3.89 (1H), 4.11 (1H),5.17 (1H), 6.48 (1H), 7.09 (1H), 7.23 (1H), 7.61 (1H), 8.60 (1H) ppm.

Example 13f(3S,6R,7S,8S,12E/Z,15S,16E)-1-Hydroxy-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1m, 1.95 g (1.89 mmol) of the compound that isproduced according to Example 13e is reacted, and after working-up andpurification, 1.56 g (1.71 mmol, 90%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.17 (27H), 0.86–0.99 (30H), 1.07–1.78 (8H), 1.11(3H), 1.26 (3H), 1.60+1.69 (3H), 1.90–2.09 (2H), 2.04 (3H), 2.29 (2H),2.48 (1H), 2.68 (1H), 3.27 (1H), 3.66 (2H), 3.80 (1H), 4.11 (2H), 5.18(1H), 6.49 (1H), 7.09 (1H), 7.22 (1H), 7.62 (1H), 8.60 (1H) ppm.

Example 13g(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-heptadeca-12,16-dienal

Analogously to Example in, 1.56 g (1.71 mmol) of the compound that isproduced according to Example 13f is reacted, and after working-up, 1.61g (max. 1.71 mmol) of the title compound is isolated as a yellow oil,which is further reacted without purification.

Example 13h(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12E,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-heptadeca-12,16-dienoicacid (B)

The solution of 1.51 g (max. 1.60 mmol) of the compound, producedaccording to Example 13g, in 57 ml of tert-butanol is mixed with 47 mlof 2-methyl-2-butene, cooled to 2° C., mixed with 12.9 ml of water, 685mg of sodium dihydrogen phosphate, 1.16 g of sodium chlorite, allowed toheat to 23° C. and stirred for 3 hours. It is poured into saturatedsodium thiosulfate solution, diluted with water and extracted severaltimes with ethyl acetate. The combined organic extracts are dried onsodium sulfate, and the residue that is obtained after filtration andremoval of the solvent is purified by chromatography on fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 749mg (807 μmol, 50%) of title compound A and 579 mg (623 μmol, 39%) oftitle compound B are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.02–0.17 (27H), 0.76–1.72 (6H), 0.88 (27H),0.94 (3H), 1.10 (3H), 1.29 (3H), 1.68 (3H), 1.91–2.60 (7H), 2.02 (3H),2.91 (1H), 3.39 (1H), 3.81 (1H), 4.11 (1H), 4.31 (1H), 5.18 (1H), 6.51(1H), 7.09 (1H), 7.23 (1H), 7.62 (1H), 8.60 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ 0.00–0.17 (27H), 0.80–0.98 (30H), 0.98–1.68 (6H),1.08 (3H), 1.30 (3H), 1.60 (3H), 1.83–2.85 (8H), 2.05 (3H), 3.39 (1H),3.79 (1H), 4.11 (1H), 4.30 (1H), 5.18 (1H), 6.48 (1H), 7.08 (1H), 8.22(1H), 7.62 (1H), 8.60 (1H) ppm.

Example 13i(3S,6R,7S,8S,12Z,15S,16E)-15-Hydroxy-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(prop-2-in-1-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 726 mg (782 μmol) of compound A that isproduced according to Example 13h is reacted, and after working-up, 657mg (max. 782 μmol) of the title compound is isolated, which is furtherreacted without purification.

Example 13j(4S,7R,8S,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 657 mg (max. 782 μmol) of the compound thatis produced according to Example 13i is reacted, and after working-upand purification, 300 mg (414 μmol, 53%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.08 (3H), 0.10 (3H), 0.15 (3H), 0.19 (3H), 0.81–2.20(8H), 0.86 (9H), 0.95 (9H), 1.02 (3H), 1.14 (3H), 1.23 (3H), 1.68 (3H),2.14 (3H), 2.33–2.82 (6H), 3.12 (1H), 4.06 (1H), 4.11 (1H), 5.02 (1H),5.19 (1H), 6.58 (1H), 7.11 (1H), 7.26 (1H), 7.63 (1H), 8.59 (1H) ppm.

Example 13k(4S,7R,18S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 140 mg (193 μmol) of the compound that isproduced according to Example 13j is reacted, and after working-up andpurification, 52 mg (105 μmol, 54%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=1.08 (3H), 1.10 (3H), 1.20–1.92 (6H), 1.42 (3H), 1.68(3H), 2.02 (1H), 2.08 (3H), 2.22–2.72 (7H), 2.86 (1H), 3.43 (1H), 3.78(1H), 4.37 (1H), 4.54 (1H), 5.12 (1H), 5.20 (1H), 6.61 (1H), 7.13 (1H),7.30 (1H), 7.69 (1H), 8.55 (1H) ppm.

Example 14(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 14a(3S,6R,7S,8S,12E,15S,16E)-15-Hydroxy-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-5-oxo-17-(2-pyridyl)-6-(prop-2-in-1-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 534 mg (575 μmol) of compound B that isproduced according to Example 13h is reacted, and after working-up, 434mg (max. 585 μmol) of the title compound is isolated, which is furtherreacted without purification.

Example 14b(4S,7R,8S,9S,13E,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 434 mg (max. 585 μmol) of the compound thatis produced according to Example 14a is reacted, and after working-upand purification, 382 mg (527 μmol, 90%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.04 (3H), 0.07–0.12 (9H), 0.85 (9H), 0.88 (9H), 0.93(3H), 1.00–2.20 (8H), 1.14 (3H), 1.22 (3H), 1.58 (3H), 2.00 (1H), 2.12(3H), 2.44–2.62 (5H), 3.19 (1H), 3.91 (1H), 4.41 (1H), 5.19 (1H), 5.29(1H), 6.53 (1H), 7.09 (1H), 7.18 (1H), 7.62 (1H), 8.59 (1H) ppm.

Example 14c(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 110 mg (152 μmol) of the compound that isproduced according to Example 14b is reacted, and after working-up andpurification, 48 mg (97 μmol, 64%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.89–1.80 (5H), 1.01 (3H), 1.06 (3H), 1.35 (3H), 1.61(3H), 1.93 (1H), 2.00 (1H), 2.10 (3H), 2.17 (1H), 2.38–2.66 (6H), 3.58(1H), 3.79 (2H), 3.88 (1H), 4.44 (1H), 5.10 (1H), 5.40 (1H), 6.59 (1H),7.13 (1H), 7.33 (1H), 7.68 (1H), 8.56 (1H) ppm.

Example 15(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 15a(4S,7R,8S,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione(A) and(4S,7R,8S,9S,13Z,16S(RS))-4,8-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione(B)

The solution of 150 mg (207 μmol) of the compound, produced according toExample 13j, in 16 ml of ethyl acetate is mixed with a catalytic amountof palladium on barium sulfate, 153 μl of pyridine, and it ishydrogenated at 23° C. under an atmosphere of hydrogen. After filtrationand removal of the solvent, the residue is purified by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. In addition to starting material, 66 mg (91 μmol, 44%) oftitle compound A and 64 mg (88 μmol, 42%) of title compound B areisolated in each case as an isolated oil.

¹H-NMR (CDCl₃) of A: δ=−0.09 (3H), 0.07 (3H), 0.11 (6H), 0.78–1.82 (7H),0.84 (9H), 0.92 (9H), 0.98 (3H), 1.09 (3H), 1.18 (3H), 1.67 (3H),2.06–2.82 (7H), 2.13 (3H), 3.11 (1H), 4.02 (1H), 4.85–5.03 (3H), 5.18(1H), 5.78 (1H), 6.57 (1H), 7.09 (1H), 7.25 (1H), 7.62 (1H), 8.59 (1H)ppm.

Example 15b(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 65.6 mg (90 mmol) of compound A that isproduced according to Example 15a is reacted, and after working-up andpurification, 24.6 mg (49 μmol, 55%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): =1.05 (6H), 1.19–1.89 (5H), 1.32 (3H), 1.69 (3H), 2.05(3H), 2.13–2.57 (6H), 2.64 (1H), 2.82 (1H), 3.33 (1H), 3.71 (2H), 4.34(1H), 4.62 (1H), 5.01 (1H), 5.05 (1H), 5.12 (1H), 5.19 (1H), 5.75 (1H),6.60 (1H), 7.12 (1H), 7.29 (1H), 7.68 (1H), 8.52 (1H) ppm.

Example 16(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 16a(4S,7R,8S,9S,13E,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 15a, 114 g (157 μmol) of the compound that isproduced according to Example 14b is reacted, and after working-up andpurification, 68 mg (94 μmol, 60%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.04 (3H), 0.08 (3H), 0.10 (3H), 0.13 (3H), 0.83–0.98(24H), 1.11 (3H), 1.15–1.96 (6H), 1.20 (3H), 2.08–2.65 (7H), 2.14 (3H),3.03 (1H), 3.88 (1H), 4.31 (1H), 4.98 (1H), 5.02 (1H), 5.22 (1H), 5.29(1H), 5.79 (1H), 6.54 (1H), 7.09 (1H), 7.20 (1H), 7.62 (1H), 8.60 (1H)ppm.

Example 16b(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 67.7 mg (93 μmol) of the compound that isproduced according to Example 16a is reacted, and after working-up andpurification, 36.8 mg (74 μmol, 80%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃) δ 0.96–2.66 (13H), 0.99 (6H), 1.28 (3H), 1.62 (3H), 2.10(3H), 3.49 (1H), 3.72 (1H), 4.01 (2H), 4.43 (1H), 4.91–5.13 (3H), 5.39(1H), 5.71 (1H), 6.58 (1H), 7.12 (1H), 7.34 (1H), 7.66 (1H), 8.53 (1H)ppm.

Example 17(1S/1R,3S(E),7S,11R(RS),11S,12S,16R/S)-7,11-Dihydroxy-10-(2,3-epoxyprop-1-yl)-3-(1-methyl-2-(2-N-oxido-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Analogously to Example 10, 36 mg (74 μmol) of the compound that isproduced according to Example 16 is reacted, and after working-up andpurification, 12 mg (22 μmol, 30%) of a mixture of two diastereomers Aand B and 20 mg (37 μmol, 50%) of a mixture of two diastereomers C and Dof the title compounds are isolated in each case as a colorless oil.

MS (FAB) m/e=546 (M⁺+1)

Example 18 (1S,3S(E),7S,10R(R orS),11S,12S,16R)-7,11-Dihydroxy-10-(2,3-epoxyprop-1-yl)-3-(1-methyl-2-(2-N-oxido-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and (1R,3S(E),7S,10R(R orS),11S,12S,16S)-7,11-dihydroxy-10-(2,3-epoxyprop-1-yl)-3-(1-methyl-2-(2-N-oxido-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

The solution of 20 mg (37 μmol) of a mixture of compounds C and D,produced according to Example 17, in 3.1 ml of anhydroustrichloromethane is mixed with a molecular sieve (4A), 789 ml ofisopropanol, 14.2 mg of tetrapropylammonium perruthenate, and it isstirred for 5 hours at 55° C. under an atmosphere of dry argon. It isconcentrated by evaporation, and the crude product that is obtained ispurified by chromatography on analytical thin-layer plates. As a mobilesolvent, a mixture of ethanol and ethyl acetate is used; as an eluant, amixture of dichloromethane and ethanol is used. 4.6 mg (8.7 μmol, 23%)of title compound A or B and 3.3 mg (6.2 μmol, 17%) of title compound Bor A are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) of A or B: δ=0.96 (3H), 1.06 (3H), 1.12–2.03 (11H), 1.22(3H), 1.30 (3H), 2.11 (3H), 2.22 (1H), 2.58 (2H), 2.76 (1H), 3.44 (1H),3.52 (1H), 3.73–3.91 (2H), 4.08–4.21 (2H), 4.47 (1H), 5.59 (1H), 6.59(1H), 7.11 (1H), 7.23 (1H), 7.63 (1H), 8.59 (1H) ppm.

¹H-NMR (CDCl₃) of B or A: δ=0.96 (3H), 1.05 (3H), 1.11–1.96 (9H), 1.23(3H), 1.31 (3H), 2.12 (3H), 2.19–2.35 (3H), 2.50–2.66 (2H), 2.78 (1H),3.50–3.69 (3H), 3.93 (1H), 4.16 (1H), 4.25 (1H), 4.41 (1H), 5.59 (1H),6.60 (1H), 7.12 (1H), 7.22 (1H), 7.64 (1H), 8.59 (1H) ppm.

Example 19 (1S/R,3S(E),7S,10R(S orR),11S,12S,16R/S)-7,11-Dihydroxy-10-(2,3-epoxyprop-1-yl)-3-(1-methyl-2-(2-N-oxido-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Analogously to Example 18, 6.3 mg (12 μmol) of compounds A and B thatare produced according to Example 17 is reacted, and after working-upand purification, 2.4 mg (4.5 μmol, 38%) of a mixture of the titlecompounds is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.95–2.22 (11H), 1.01 (3H), 1.10 (3H), 1.27 (3H), 1.31(3H), 2.11 (3H), 2.34 (1H), 2.45–2.57 (2H), 2.90 (1H), 3.39–3.87 (4H),4.01–4.37 (3H), 5.49 (1H), 6.62 (1H), 7.13 (1H), 7.24 (1H), 7.66 (1H),8.58 (1H) ppm.

Example 20 (4S,7R,8S,9S,13Z,16S(R orS))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione(A) and (4S,7R,8S,9S,13Z,16S(S orR))-4,8-dihydroxy-16-(1-methyl-2-(2-pyridyl)ethyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione(B)

Analogously to Example 1, 7.0 mg (9.6 μmol) of compounds B that areproduced according to Example 15a is reacted, and after working-up andpurification, 1.4 mg (2.8 μmol, 29%) of title compound A and 1.7 mg (3.4μmol, 35%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=0.88 (1H), 0.92 (3H), 1.04 (3H), 1.07 (3H),1.18–2.57 (14H), 1.30 (3H), 1.68 (3H), 2.91 (1H), 3.17 (1H), 3.28 (1H),3.68 (1H), 4.47 (1H), 4.91–5.10 (4H), 5.70 (1H), 7.13–7.22 (2H), 7.68(2H), 8.46 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=1.00 (6H), 1.05 (3H), 1.10–2.59 (15H), 1.33 (3H),1.63 (3H), 2.93 (1H), 3.11 (1H), 3.28 (1H) 3.63 (1H), 4.44 (1H),4.91–5.12 (4H), 5.79 (1H), 6.39 (1H), 7.18 (2H), 7.67 (1H), 8.46 (1H)ppm.

Example 21(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dioneExample 21a (2E/Z)-3-(2-Methyl-benzoxazol-5-yl)-2-propenoic acid ethylester

The suspension of 58 g (346 mmol) of 5-chloro-2-methylbenzoxazole, 200ml of dimethylformamide, 57 g of sodium iodide and 16.2 g of nickel(II)bromide is heated for 4 hours to 150° C. After cooling, it is mixed with42 ml of acrylic acid ethyl ester, 53 ml of triethylamine, 998 mg oftris-(dibenzylidene acetone)-dipalladium (O), 36.4 g oftriphenylphosphine, and it is heated for three days to 150° C. Thecooled mixture is poured into water, acidified and extracted severaltimes with ethyl acetate. The combined organic extracts are washed withsaturated sodium chloride solution, dried on sodium sulfate, and theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 6.4 g (28 mmol, 8%) of thetitle compound is isolated as a crystalline solid.

¹H-NMR (CDCl₃): δ=1.33 (3H), 2.64 (3H), 4.28 (2H), 6.42 (1H), 7.47 (2H),7.78 (1H), 7.81 (1H) ppm.

Example 21b (2-Methylbenzoxazol-5-yl)-carbaldehyde

The solution of 9.5 g (41 mmol) of the compound, produced according toExample 21a, in ml of tetrahydrofuran, is mixed with ml of water, ml ofa 2.5% solution of osmium tetroxide in tert-butanol, g of sodiumperiodate, and it is stirred for 6 hours at 23° C. It is poured ontosaturated sodium thiosulfate solution and extracted several times withethyl acetate. The combined organic extracts are washed with saturatedsodium chloride solution, dried on sodium sulfate, and the residue thatis obtained after filtration and removal of the solvent is purified bychromatography on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate. 4.86 g (30 mmol, 74%) of the titlecompound is isolated as a crystalline solid.

¹H-NMR (CDCl₃): δ=2.69 (3H), 7.60 (1H), 7.90 (1H), 8.16 (1H), 10.08 (1H)ppm.

Example 21c(3RS)-3-(2-Methyl-benzoxazol-5-yl)-1-[(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-on-3-yl]-3-hydroxypropyl-1-one

50 ml of a 2.4 molar solution of n-butyllithium in n-hexane is added indrops at −30° C. under an atmosphere of dry argon to the solution of14.1 ml of diisopropylamine in 670 ml of anhydrous tetrahydrofuran, itis stirred for 20 minutes, cooled to −70° C. and mixed within 4.5 hourswith the solution of 19.8 g(4S,5R)-3-acetyl-4-methyl-5-phenyloxazolidin-2-one in 670 ml oftetrahydrofuran. After 1 hour, the solution of 4.86 g (30.1 mmol) of thecompound, produced according to Example 21b, in 175 ml oftetrahydrofuran is added in drops within 1.5 hours, and it is stirredfor 1 hour at −70° C. It is poured onto a saturated ammonium chloridesolution, extracted several times with ethyl acetate, the combinedorganic extracts are washed with saturated sodium chloride solution anddried on sodium sulfate. The residue that is obtained after filtrationand removal of the solvent is purified by chromatography on fine silicagel with a gradient system that consists of n-hexane and ethyl acetate.11.3 g (29.7 mmol, 98%) of the title compound is isolated as a colorlessoil.

Example 21d(3S)-3-(2-Methyl-benzoxazol-5-yl)-1-[([(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-on-3-yl]-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-propyl-1-one(A) and(3R)-3-(2-methyl-benzoxazol-5-yl)-1-[(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-on-3-yl]-3-[(dimethyl(1,1-dimethylethyl)silyl]oxy]-propyl-1-one(B)

The solution of 12.5 g (32.8 mmol) of the compound, produced accordingto Example 21c, in 110 ml of anhydrous dichloromethane is cooled underan atmosphere of dry argon to −70° C., mixed with 7.8 ml of 2,6-lutidineand 13.9 ml of trifluoromethanesulfonicacid-tert-butyldimethylsilylester, and it is stirred for 1 hour. It ispoured onto a saturated sodium bicarbonate solution, extracted severaltimes with dichloromethane, the combined organic extracts are washedwith saturated sodium chloride solution and dried on sodium sulfate. Theresidue that is obtained after filtration and removal of the solvent isseparated by chromatography on fine silica gel with a gradient systemthat consists of n-hexane, ethyl acetate and ethanol. 8.9 g (18.0 mmol,55%) of title compound A is isolated as a crystalline solid, and 2.9 g(5.9 mmol, 18%) of title compound B is isolated as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.19 (3H), 0.02 (3H), 0.82 (9H), 0.88 (3H), 2.61(3H), 3.19 (1H), 3.51 (1H), 4.69 (1H), 5.36 (1H), 5.55 (1H), 7.21–7.44(7H), 7.64 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.19 (3H), 0.04 (3H), 0.85 (9H), 0.88 (3H), 2.63(3H), 3.04 (1H), 4.67 (1H), 4.77 (1H), 5.39 (1H), 5.63 (1H), 7.21–7.46(7H), 7.67 (1H) ppm.

Example 21e(3S)-3-(2-Methyl-benzoxazol-5-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-propionicacid ethyl ester

The solution of 13.9 g (28.2 mmol) of the compound, produced accordingto Example 21d, in 140 ml of anhydrous ethanol is mixed at 23° C. underan atmosphere of dry argon with 7.1 ml of titanium tetraethylate, and itis heated for 3 hours to 85° C. It is concentrated by evaporation, andthe residue is purified by chromatography on fine silica gel with agradient system that consists of n-hexane and ethyl acetate. 10.1 g(27.8 mmol, 99%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.20 (3H), 0.02 (3H), 0.82 (9H), 1.26 (3H), 2.55(1H), 2.62 (3H), 2.76 (1H), 4.12 (2H), 5.26 (1H), 7.29 (1H), 7.40 (1H),7.62 (1H) ppm.

Example 21f(3S)-3-(2-Methyl-benzoxazol-5-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-propan-1-ol

The solution of 10.1 g (27.8 mmol) of the compound, produced accordingto Example 21e, in ml of anhydrous dichloromethane, is cooled under anatmosphere of dry argon to −78° C., mixed with 58 ml of a 1.2 molarsolution of diisobutylaluminum hydride in toluene, and it is stirred for1 more hour. It is mixed with 16 ml of isopropanol, 32 ml of water,allowed to heat to 23° C. and stirred until a fine-grained precipitatehas formed. After filtration and removal of the solvent, 7.2 g (22.4mmol, 81%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.18 (3H), 0.07 (3H), 0.89 (9H), 1.97 (2H), 2.35(1H), 2.66 (3H), 3.73 (2H), 5.06 (1H), 7.28 (1H), 7.42 (1H), 7.60 (1H)ppm.

Example 21g(3S)-3-(2-Methyl-benzoxazol-5-yl)-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-iodo-propane

The solution of 2.83 g of triphenylphosphine in 40 ml of anhydrousdichloromethane is mixed at 23° C. under an atmosphere of dry argon with737 mg of imidazole, 2.71 g of iodine, and the solution of 2.65 g (8.2mmol) of the compound, produced according to Example 21f, in 30 ml ofdichloromethane, is added in drops while being cooled. It is stirred for1 hour and purified directly by chromatography on fine silica gel with agradient system that consists of n-hexane and ethyl acetate. 2.3 g (5.3mmol, 65%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃) δ=−0.20 (3H), 0.06 (3H), 0.85 (9H), 2.10 (1H), 2.21 (1H),2.61 (3H), 3.11 (1H), 3.23 (1H), 4.82 (1H), 7.22 (1H), 7.39 (1H), 7.59(1H) ppm.

Example 21h(3S)-3-(2-Methyl-benzoxazol-5-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-propane-1-triphenylphosphoniumiodide

2.3 g (5.3 mmol) of the compound that is produced according to Example21g is mixed with 2.9 ml of ethyldiisopropylamine, 17.5 g oftriphenylphosphine, and it is heated for 4 hours to 85° C. The oilyresidue is purified by chromatography on fine silica gel with a gradientsystem that consists of n-hexane and ethyl acetate. 3.3 g (4.8 mmol,89%) of the title compound is isolated as a crystalline solid.

¹H-NMR (CDCl₃): =−0.19 (3H), 0.12 (3H), 0.84 (9H), 1.89 (1H), 2.09 (1H),2.60 (3H), 3.41. (1H), 4.06 (1H), 5.37 (1H), 7.38 (1H), 7.49 (1H), 7.59(1H), 7.62–7.84 (15H) ppm.

Example 21i(2S,6E/Z,9S)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-9-(2-methyl-benzoxazol-5-yl)-1-(tetrahydropyran-2-yloxy)-2,6-dimethyl-non-6-ene

The solution of 2.3 g (3.3 mmol) of the compound, produced according toExample 21h, in 15 ml of anhydrous tetrahydrofuran is mixed under anatmosphere of dry argon at 0° C. with 5 ml of a 1.0 molar solution ofsodium hexamethyldisilazane in tetrahydrofuran, the solution of 513 mg(2.25 mmol) of (2S)-2-methyl-6-oxo-heptane-1-(tetrahydropyran-2-yloxy),which was produced analogously to the process described in DE 197 51200.3, is added in drops in 15 ml of tetrahydrofuran, allowed to heat to23° C. and reacted for 3 more hours. It is poured onto a saturatedammonium chloride solution, extracted several times with ethyl acetate,the combined organic extracts are washed with saturated sodium chloridesolution and dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is separated by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 506 mg (1.0 mmol, 44%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃) δ=−0.15 (3H), 0.01 (3H), 0.80–0.92 (12H), 1.02 (1H),1.19–1.97 (12H), 1.46+1.62 (3H), 2.21–2.48 (2H), 2.60 (3H), 3.10+3.19(1H), 3.40–3.61 (2H), 3.82 (1H), 4.53 (1H), 4.69 (1H), 5.11 (1H), 7.22(1H), 7.37 (1H), 7.57 (1H) ppm.

Example 21j(2S,6E/Z,9S)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-9-(2-methyl-benzoxazol-5-yl)-1-hydroxy-2,6-dimethyl-non-6-ene

Analogously to Example 1k, 447 mg (0.87 mmol) of the compound that isproduced according to Example 21i is reacted, and after working-up andpurification, 298 mg (0.69 mmol, 79%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.12 (3H), 0.01 (3H), 0.82–0.92 (12H), 1.01 (1H),1.16–1.67 (4H), 1.44+1.63 (3H), 1.83–1.98 (2H), 2.18 (1H), 2.33 (1H),2.44 (1H), 2.62 (3H), 3.31–3.53 (2H), 4.71 (1H), 5.07+5.13 (1H),7.24+7.29 (1H), 7.39 (1H), 7.53+7.58 (1H) ppm.

Example 21k(2S,6E/Z,9S)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-9-(2-methyl-benzoxazol-5-yl)-1-oxo-2,6-dimethyl-non-6-ene

Analogously to Example 1n, 272 mg (0.63 mmol) of the compound that isproduced according to Example 21j is reacted, and after working-up andpurification, 236 mg (0.55 mmol, 87%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.16 (3H), 0.01 (3H), 0.84 (9H) 1.02+1.05 (3H),1.13–2.50 (9H), 1.44+1.61 (3H), 2.61 (3H), 4.71 (1H), 5.13 (1H), 7.21(1H), 7.37 (1H), 7.55 (1H), 9.54 (1H) ppm.

Example 21l(4S(4R,5S,6S,10E/Z,13S))-4-(13-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-(prop-2-en-1-yl)-13-(2-methyl-benzoxazol-5-yl)-3-oxo-5-hydroxy-2,6,10-trimethyl-tridec-10-en-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10E/Z,13S))-4-(13-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(prop-2-en-1-yl)-13-(2-methyl-benzoxazol-5-yl)-3-oxo-5-hydroxy-2,6,10-trimethyl-tridec-10-en-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1c, 236 mg (0.55 mmol) of the compound that isproduced according to Example 21k is reacted with 433 mg (1.80 mmol) of(4S)-4-(2-methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-[1,3]dioxane, whichwas produced analogously to the process that is described in DE 197 51200.3, and after working-up and purification, in addition to startingmaterial, 221 mg (0.33 mmol, 60%) of title compound A and 72 mg (0.11mmol, 20%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=−0.13 (3H), 0.01 (3H), 0.78–0.88 (12H), 0.96(3H), 1.04 (1H), 1.11–2.52 (12H), 1.23 (3H), 1.31 (3H), 1.39 (3H),1.47+1.64 (3H), 2.62 (3H), 2.90+2.98 (1H), 3.32 (1H), 3.47 (1H), 3.87(1H), 3.97 (1H), 4.13 (1H), 4.70 (1H), 4.98 (1H), 5.03 (1H), 5.12 (1H),5.71 (1H), 7.22 (1H), 7.38 (1H), 7.56 (1H) ppm.

Example 21m(3S,6R,7S,8S,12E/Z,15S)-15-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-(prop-2-en-1-yl)-1,3,7-trihydroxy-4,4,8,12-tetramethyl-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-en-5-one

Analogously to Example 1k, 221 mg (0.33 mmol) of compound A that isproduced according to Example 211 is reacted, and after working-up andpurification, 163 mg (0.26 mmol, 78%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.15 (3H), 0.01 (3H), 0.79–0.90 (12H), 1.05 (3H),1.17–2.59 (13H), 1.20+1.24 (3H), 1.43+1.62 (3H), 2.62+2.64 (0.3H),2.81+3.07 (1H), 3.25–3.70 (3H), 3.86 (2H), 4.08 (2H), 4.68 (1H),4.92–5.19 (3H), 5.69 (1H), 7.25+7.29 (1H), 7.39 (1H), 7.48+7.52 (1H)ppm.

Example 21n(3S,6R,7S,8S,12E/Z,15S)-6-(Prop-2-en-1-yl)-1,3,7,15-tetrakis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-en-5-one

Analogously to Example 1l, 163 mg (0.26 mmol) of the compound that isproduced according to Example 21m is reacted, and after working-up andpurification, 236 mg (0.24 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.06 (3H), −0.04–0.08 (21H), 0.79–0.93 (39H),0.96–1.66 (7H), 1.01 (3H), 1.17 (3H), 1.47+1.62 (3H), 1.88 (2H),2.18–2.52 (4H), 2.61 (3H), 3.11 (1H), 3.53 (1H), 3.63 (1H), 3.73 (1H),3.84 (1H), 4.68 (1H), 4.91 (1H), 4.97 (1H), 5.12 (1H), 5.72 (1H), 7.21(1H), 7.36 (1H), 7.56 (1H) ppm.

Example 21o(3S,6R,7S,8S,12E/Z,15S)-1-Hydroxy-6-(prop-2-en-1-yl)-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-en-5-one

Analogously to Example 1m, 236 mg (0.24 mmol) of the compound that isproduced according to Example 21n is reacted, and after working-up andpurification, 146 mg (0.17 mmol, 71%) of the title compound is isolatedas a colorless oil.

Example 21p(3S,6R,7S,8S,12E/Z,15S)-5-Oxo-6-(prop-2-en-1-yl)-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-enal

Analogously to Example 1n, 146 mg (0.17 mmol) of the compound that isproduced according to Example 210 is reacted, and after working-up andpurification, 143 mg (0.17 mmol, 98%) of the title compound is isolatedas a colorless oil.

Example 21q (3S,6R,7S,8S,12Z,15S)-5-Oxo-6-(prop-2-en-1-yl)-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl-5-(2-methyl-benzoxazol-5-yl)-pentadec-12-enoicacid (A) and(3S,6R,7S,8S,12E,15S)-5-oxo-6-(prop-2-en-1-yl)-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl)-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-enoicacid (B)

The solution of 143 mg (0.17 mmol) of the compound, produced accordingto Example 21p, in 5 ml of tert-butanol is mixed at 0° C. with thesolution of 1.1 ml of 2-methyl-2-butene in 3.6 ml of tetrahydrofuran,1.3 ml of water, 67 mg of sodium dihydrogen phosphate, 117 mg of sodiumchlorite, and it is stirred for 2 hours. It is poured onto a saturatedsodium thiosulfate solution, extracted several times with ethyl acetate,the combined organic extracts are washed with saturated sodium chloridesolution and dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is separated by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 58 mg (66 mmol, 39%) of title compound A and 52 mg (60μmol, 35%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=−0.13 (3H), −0.02 (6H), 0.04 (6H), 0.12 (3H),0.80–0.92 (27H), 0.96 (3H), 1.06 (3H), 1.09–1.96 (7H), 1.15 (3H), 1.70(3H), 2.13–2.60 (7H), 2.62 (3H), 3.20 (1H), 3.66 (1H), 4.43 (1H), 4.72(1H), 4.92 (1H), 4.99 (1H), 5.26 (1H), 5.70 (1H), 7.34 (1H), 7.40 (1H),7.89 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.11 (3H), 0.02 (6H), 0.07 (3H), 0.10 (3H), 0.16(3H), 0.86–0.94 (30H), 0.90–2.05 (8H), 1.12 (3H), 1.19 (3H), 1.39 (3H),2.23–2.60 (6H), 2.63 (3H), 3.21 (1H), 3.79 (1H), 4.36 (1H), 4.68 (1H),4.98 (1H), 5.01 (1H), 5.10 (1H), 5.77 (1H), 7.36 (1H), 7.41 (1H), 7.54(1H) ppm.

Example 21r(3S,6R,7S,8S,12Z,15S)-15-Hydroxy-5-oxo-6-(prop-2-en-1-yl)-3,7-bis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-enoicacid

Analogously to Example 1p, 58 mg (66 μmol) of compound A that isproduced according to Example 21q is reacted, and after working-up, 52mg (max. 66 μmol) of the title compound is isolated, which is furtherreacted without purification.

Example 21s (4S,7R,8S,9S,13Z16S)-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(2-methyl-benzoxazol-5-yl)-7-(prop-2-en-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 52 mg (max. 66 μmol) of the compound that isproduced according to Example 21r is reacted, and after working-up andpurification, 42 mg (57 μmol, 86%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=−0.08 (3H), 0.09 (6H), 0.14 (3H), 0.77–1.88 (7H), 0.85(9H), 0.93 (9H), 1.01 (3H), 1.09 (3H), 1.15 (3H), 1.71 (3H), 2.10–2.75(6H), 2.62 (3H), 2.91 (1H), 3.11 (1H), 4.00 (1H), 4.92 (1H), 4.99 (1H),5.19 (1H), 5.57 (1H), 5.79 (1H), 7.32 (1H), 7.44 (1H), 7.68 (1H) ppm.

Example 21t(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-7-(prop-2-en-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 42 mg (57 μmol) of the compound that isproduced according to Example 21s is reacted, and after working-up andpurification, 19 mg (37 μmol, 65%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=1.02 (3H), 1.08 (3H), 1.14–1.97 (6H), 1.22 (3H), 1.70(3H), 2.22–2.60 (7H), 2.62 (3H), 2.78–2.95 (2H), 3.36 (1H), 3.78 (1H),4.10 (1H), 5.03 (1H), 5.09 (1H), 5.19 (1H), 5.76 (1H), 5.85 (1H), 7.28(1H), 7.43 (1H), 7.63 (1H) ppm.

Example 22(4S,7R,8S,9S,13E,16S)-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-7-(prop-2-en-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneExample 22a(3S,6R,7S,8S,12E,15S)-15-Hydroxy-5-oxo-6-(prop-2-en-1-yl)-3,7-bis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,8,12-tetramethyl-15-(2-methyl-benzoxazol-5-yl)-pentadec-12-enoicacid

Analogously to Example 1p, 52 mg (60 μmol) of compound B that isproduced according to Example 21q is reacted, and after working-up, 46mg (max. 60 μmol) of the title compound is isolated, which is furtherreacted without purification.

Example 22b(4S,7R,8S,9S,13E,16S)-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(2-methyl-benzoxazol-5-yl)-7-(prop-2-en-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 46 mg (max. 60 μmol) of the compound that isproduced according to Example 22a is reacted, and after working-up andpurification, 32 mg (43 μmol, 72%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.03–0.11 (12H), 0.89 (9H), 0.91 (9H), 0.94–1.96 (6H),0.98 (3H), 1.12 (3H), 1.21 (3H), 1.59 (3H), 2.10–2.76 (7H), 2.63 (3H),3.08 (1H), 3.91 (1H), 4.31 (1H), 5.02 (1H), 5.07 (1H), 5.29 (1H), 5.79(1H), 5.89 (1H), 7.30 (1H), 7.42 (1H), 7.62 (1H) ppm.

Example 22c(4S,7R,8S,9S,13E,16S)-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-7-(prop-2-en-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 32 mg (43 μmol) of the compound that isproduced according to Example 22b is reacted, and after working-up andpurification, 15 mg (29 μmol, 68%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.99 (3H), 1.02 (3H), 1.27 (3H), 1.38–1.99 (6H), 1.64(3H), 2.18 (1H), 2.23–2.76 (6H), 2.62 (3H), 3.34 (1H), 3.49 (2H), 3.75(1H), 4.32 (1H), 4.96–5.08 (3H), 5.73 (1H), 5.98 (1H), 7.23 (1H), 7.42(1H), 7.67 (1H) ppm.

Example 23(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneExample 23a(4S(4R,5S,6S,10E/Z,13S,14Z))-4-(13-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-(prop-2-in-1-yl)-14-fluoro-15-(2-methylthiazol-4-yl)-3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-(10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10E/Z,13S,14Z))-4-(13-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(prop-2-in-1-yl)-14-fluoro-15-(2-methylthiazol-4-yl)-3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1c, 2.89 g (6.57 mmol) of(2S,6E/Z,9S,10Z)-9-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-10-fluoro-11-(2-methyl-4-thiazolyl)-2,6-dimethylundeca-6,10-dienal,which was produced analogously to the process that is described in DE19907480.1, is reacted with 5.09 g (16.4 mmol) of(4S)-4-(2-methyl-3-oxo-7-trimethylsilyl-hept-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane,which was produced according to the process described in DE 19751200.3,and after working-up and purification, in addition to starting material,3.26 g (4.35 μmol, 66%) of title compound A as well as 602 mg (0.80mmol, 12%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=0.03–0.13 (15H), 0.82–0.92 (12H), 0.97–2.08(12H), 1.06 (3H), 1.30 (6H), 1.38 (3H), 1.58+1.65 (3H), 2.33–2.47 (3H),2.55 (1H), 2.70 (3H), 3.44 (1H), 3.52 (1H), 3.80–4.28 (2H), 5.13 (1H),6.03 (1H), 7.32 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.05–0.65 (15H), 0.88–0.99 (12H), 1.02–1.73 (8H),1.18 (6H), 1.32 (3H), 1.41 (3H), 1.60+1.69 (3H), 1.90–2.08 (2H),2.33–2.58 (4H), 2.70 (3H), 3.43 (1H), 3.60 (1H), 3.79–4.26 (4H), 5.18(1H), 6.05 (1H), 7.33 (1H) ppm.

Example 23b(3S,6R,7S,8S,12E/Z,15S,16Z)-15-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-16-fluoro-1,3,7-trihydroxy-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1k, 3.26 g (4.35 mmol) of compound A that isproduced according to Example 23a is reacted, and after working-up andpurification, in addition to starting material, 2.44 g (3.43 μmol, 79%)of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): =0.03–0.15 (15H), 0.85–0.95 (12H), 0.98–2.08 (8H), 1.14(3H), 1.26 (3H), 1.58+1.67 (3H), 2.31–2.49 (3H), 2.59–2.76 (2H), 2.72(3H), 2.89 (1H), 3.06 (1H), 3.42 (1H), 3.47 3.58 (2H), 3.88 (2H),4.08–4.22 (2H), 5.11+5.18 (1H), 5.98 (1H), 7.33 (1H) ppm.

Example 23c(3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-1,3,7,15-tetrakis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1l, 2.77 g (3.90 mmol) of the compound that isproduced according to Example 23b is reacted, and after working-up andpurification, 3.48 g (3.31 mmol, 85%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.15 (33H), 0.83–0.97 (39H), 1.00–1.75 (7H), 1.07(3H), 1.27 (3H), 1.60+1.68 (3H), 1.88–2.03 (2H), 2.31–2.48 (2H), 2.51(2H), 2.70 (3H), 3.29 (1H), 3.52–3.71 (2H), 3.29 (1H), 3.89 (1H), 4.19(1H), 5.15 (1H), 6.06 (1H), 7.33 (1H) ppm.

Example 23d(3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-1-hydroxy-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1m, 3.48 g (3.31 mmol) of the compound that isproduced according to Example 23c is reacted, and after working-up andpurification, 2.36 g (2.5 mmol, 76%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.18 (27H), 0.83–0.99 (30H), 1.01–1.80 (7H), 1.12(3H), 1.27 (3H), 1.60+1.68 (3H), 1.86–2.07 (3H), 2.83–2.52 (3H), 2.64(1H), 2.70 (3H), 3.26 (1H), 3.66 (2H), 3.80 (1H), 4.10 (1H), 4.20 (1H),5.16 (1H), 6.06 (1H), 7.32 (1H) ppm.

Example 23e(3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-5-oxo-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dienal

Analogously to Example 1n, 2.36 g (2.51 mmol) of the compound that isproduced according to Example 23d is reacted, and after working-up andpurification, 2.25 g (2.40 mmol, 96%) of the title compound is isolatedas a colorless oil.

Example 23f(3S,6R,7S,8S,12Z,15S,16Z)-16-Fluoro-5-oxo-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12E,15S,16Z)-16-fluoro-5-oxo-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-1,2,16-dienoicacid (B)

Analogously to Example 22q, 2.25 g (2.40 mmol) of the compound that isproduced according to Example 23e is reacted, and after working-up andpurification, 960 mg (1.01 mmol, 42%) of title compound A as well as 937mg (0.98 mmol, 41%) of title compound are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.02–0.17 (27H), 0.89 (27H), 0.94 (3H),1.08–1.67 (6H), 1.18 (3H), 1.22 (3H), 1.70 (3H), 1.89 (1H), 2.12 (1H),2.28–2.53 (5H), 2.61 (1H), 2.69 (3H), 3.31 (1H), 3.71 (1H), 4.20 (1H),4.38 (1H), 5.18 (1H), 6.40 (1H), 7.36 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.01–0.18 (27H), 0.84–0.97 (30H), 1.00–1.55(6H), 1.20 (3H), 1.23 (3H), 1.59 (3H), 1.82–2.05 (2H), 2.25–2.60 (4H),2.65 (1H), 2.70 (3H), 3.33 (1H), 3.76 (1H), 4.16 (1H), 4.38 (1H), 5.13(1H), 6.12 (1H), 7.38 (1H) ppm.

Example 23g(3S,6R,7S,8S,12Z,15S,16Z)-16-Fluoro-5-oxo-3,7-bis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-15-hydroxy-6-(prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 960 mg (1.01 mmol) of compound A that isproduced according to Example 23f is reacted, and after working-up, 898mg (max. 1.01 mmol) of the title compound is isolated, which is furtherreacted without purification.

Example 23h(4S,7R,8S,9S,13Z,16S(Z))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-fluoro-2-(2-methylthiazol-4-yl)-ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, a total of 896 mg (max. 1.01 mmol) of thecompound that is produced according to Example 23b is reacted in severalportions, and after working-up and purification, 480 mg (0.64 mmol, 64%)of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.10 (3H), 0.12 (3H0, 0.15 (3H), 0.19 (3H), 0.80–1.8396H), 0.85 (9H), 0.94 (9H), 1.01 (3H), 1.18 (3H), 1.23 (3H), 1.68 (3H),2.08 (1H), 2.22–2.89 (7H), 2.69 (3H), 3.09 (1H), 4.00–4.12 (2H),5.07–5.21 (2H), 6.13 (1H), 7.36 (1H) ppm.

Example 23i(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 60 mg (80 μmol) of the compound that isproduced according to Example 23h is reacted, and after working-up andpurification, 28 mg (54 μmol, 67%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=1.05 (3H), 1.11 (3H), 1.18–1.42 (3H), 1.38 (3H),1.56–1.97 (3H), 1.90 (3H), 2.05 (1H), 2.28 (1H), 2.33–2.66 (6H), 2.69(3H), 2.79 (1H), 3.30 (1H), 3.38 (1H), 3.79 (1H), 4.21 (1H), 5.12 (1H),5.46 (1H), 6.19 (1H), 7.36 (1H) ppm.

Example 24(4S,7R,8S,9S,13E,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-12,6-dioneExample 24a(3S,6R,7S,8S,12E,15S,16Z)-16-Fluoro-5-oxo-3,7-bis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-15-hydroxy-6-(prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 937 mg (0.98 mmol) of compound B that isproduced according to Example 23f is reacted, and after working-up, 914mg (max. 0.98 mmol) of the title compound is isolated, which is furtherreacted without purification.

Example 24b(4S,7R,8S,9S,13E,16S(Z))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-fluoro-2-(2-methylthiazol-4-yl)-ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 914 mg (max. 0.98 mmol) of the compound thatis produced according to Example 24a is reacted, and after working-upand purification, 451 mg (603 μmol, 62%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.02–0.12 (12H), 0.79–1.73 (5H), 0.89 (18H), 0.96(3H), 1.12 (3H), 1.22 (3H), 1.58 (3H), 1.91 (1H), 2.01 (1H), 2.11 (1H),2.39–2.80 (6H), 2.69 (3H), 3.15 (1H), 3.91 (1H), 4.33 (1H), 5.17 (1H),5.42 (1H), 6.12 (1H), 7.36 (1H) ppm.

Example 24c(4S,7R,8S,9S,13E,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methylthiazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 451 mg (603 μmol) of the compound that isproduced according to Example 24b is reacted, and after working-up andpurification, 170 mg (327 μmol, 54%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.86 (1H), 1.00 (3H), 1.03 (3H), 1.26–2.23 (7H), 1.33(3H), 1.60 (3H), 2.41–2.62 (6H), 2.69 (3H), 3.59 (1H), 3.79 (1H),4.02–4.19 (2H), 4.39 (1H), 5.11 (1H), 5.54 (1H), 6.17 (1H), 7.37 (1H)ppm.

Example 25(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-10-(prop-2-in-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(Z),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-10-(prop-2-in-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

The solution of 50 mg (96 μmol) of the compound, produced according toExample 23, in 4.5 ml of acetonitrile is mixed at 0° C. with 554 μl of a0.1 M aqueous solution of ethylenediamine tetraacetate, 638 μl oftrifluoroacetone, 260 mg of sodium bicarbonate, 150 mg of oxone, and itis stirred for 1.5 hours at 23° C. It is mixed with sodium thiosulfatesolution, extracted several times with ethyl acetate, the combinedorganic extracts are washed with saturated sodium chloride solution,dried on sodium sulfate, and the residue is purified by chromatographyon analytic thin-layer plates. As a mobile solvent, a mixture thatconsists of dichloromethane and isopropanol is used; as an eluant, amixture that consists of dichloromethane and methanol is used. 29 mg (54μmol, 56%) of title compound A as well as 9 mg (17 μmol, 18%) of titlecompound B are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=1.01 (3H), 1.08 (3H), 1.22–1.81 (7H), 1.28 (3H),1.39 (3H), 2.01 (1H), 2.04 (1H), 2.19 (1H), 2.40–2.76 (5H), 2.69 (3H),2.91 (1H), 3.60 (1H), 3.80 (1H), 4.19 (1H), 4.31 (1H), 5.70 (1H), 6.23(1H), 7.38 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.97 (3H), 1.08 (3H), 1.19–1.96 (8H), 1.25 (3H),1.42 (3H), 1.99 (1H), 2.28 (1H), 2.42–2.62 (4H), 2.70 (3H), 2.98 (1H),3.04 (1H), 3.49 (1H), 3.62 (1H), 4.04 (1H), 4.23 (1H), 5.80 (1H), 6.21(1H), 7.38 (1H) ppm.

Example 26(1S,3S(Z),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-10-(prop-2-in-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(Z),7S,10R,1S,12S,16R)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-thiazolyl)ethenyl)-10-(prop-2-in-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B) and(1SR,3S(Z),7S,10R,11S,12S,16SR)-7,11-dihydroxy-3-(1-fluoro-2-(2-methyl-4-(N-oxido)-thiazolyl)ethenyl)-10-(prop-2-in-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(C)

Analogously to Example 25, 80 mg (154 μmol) of the compound that isproduced according to Example 24 is reacted, and after working-up andpurification, 21 mg (39 μmol, 25%) of title compound A, 31 mg (58 μmol,38%) of title compound B as well as 3 mg (6 μmol, 4%) of title compoundsC are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) of A or B: δ=0.96 (3H), 1.08 (3H), 1.18–1.85 (7H), 1.22(3H), 1.38 (3H), 1.99 (1H), 2.09 (1H), 2.20 (1H), 2.40 (1H), 2.51–2.72(3H), 2.68 (3H), 2.99 (1H), 3.13 (1H), 3.53 (1H), 3.75 (1H), 3.82 (1H),4.30 (1H), 5.66 (1H), 6.21 (1H), 7.37 (1H) ppm.

¹H-NMR (CDCl₃) of B or A: δ=0.93 (3H), 1.04 (3H), 1.11–1.81 (7H), 1.28(3H), 1.41 (3H), 1.99 (1H), 2.06–2.23 (2H), 2.43 (1H), 2.51–2.72 (4H),2.69 (3H), 2.87 (1H), 3.55 (1H), 3.85 (1H), 4.19 (1H), 4.31 (1H), 5.66(1H), 6.24 (1H), 7.39 (1H) ppm.

¹H-NMR of C (CDCl₃): δ=0.95+0.99 (3H), 1.08+1.10 (3H), 1.13–2.77 (14H),1.22+1.26 (3H), 1.45+1.51 (3H), 2.59 (3H), 2.95 (1H), 3.52–3.86 (2H),4.13+5.41 (1H), 4.43–4.70 (2H), 5.63+5.72 (1H), 6.56+6.59 (1H),7.41+7.46 (1H) ppm.

Example 27(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneExample 27a 4-(2-Methyloxazolyl)-carbaldehyde

The solution of 36.6 g (236 mmol) of 4-(2-methyloxazolyl)-carboxylicacid ethyl ester in 795 ml of anhydrous dichloromethane is cooled underan atmosphere of dry argon to −78° C., mixed with 378 ml of a 1.0 molarsolution of diisobutylaluminum hydride in n-hexane, and it is stirredfor 1 more hour. It is mixed with 96 ml of isopropanol, 160 ml of water,allowed to heat to 23° C. and stirred until a fine-grained precipitatehas formed. After filtration and removal of the solvent, 24.7 g (222mmol, 94%) of the title compound is isolated as a pale yellow oil.

¹H-NMR (CDCl₃): δ=2.53 (3H), 8.17 (1H), 9.90 (1H) ppm.

Example 27b (2Z)-3-(2-Methyloxazol-4-yl)-2-fluoro-2-propenoic acid ethylester (A) and (2E)-3-(2-methyloxazol-4-yl)-2-fluoro-2-propenoic acidethyl ester (B)

The solution of 106 g of 2-fluoro-2-phosphonoacetic acid triethyl esterin 224 ml of ethylene glycol dimethyl ether is added in drops under anatmosphere of dry argon at 0° C. to 19.1 g of a 55% sodium hydridedispersion in 224 ml of anhydrous ethylene glycol dimethyl ether, and itis stirred for one more hour. Then, it is mixed with the solution of26.4 g (238 mmol) of the compound, produced according to Example 27a, in224 ml of ethylene glycol dimethyl ether, and it is allowed to heatwithin 1 hour to 23° C. It is poured onto a saturated ammonium chloridesolution, extracted several times with ethyl acetate, the combinedorganic extracts are washed with saturated sodium chloride solution anddried on sodium sulfate. The residue that is obtained after filtrationand removal of the solvent is purified by chromatography on fine silicagel with a gradient system that consists of n-hexane and ethyl acetate.24.8 g (125 mmol, 52%) of title compound A is isolated as a crystallinesolid, and 12.5 g (63 mmol, 26%) of title compound B is isolated as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=1.37 (3H), 2.49 (3H), 4.32 (2H), 6.91 (1H), 7.94(1H) ppm.

¹H-NMR (CDCl₃) of B: δ=1.39 (3H), 2.47 (3H), 4.36 (2H), 6.75 (1H), 8.53(1H) ppm.

Example 27c (2Z)-3-(2-Methyloxazol-4-yl)-2-fluoro-2-propenoic acid ethylester

The solution of 24.4 g (123 mmol) of compound B, produced according toExample 27b, in 130 ml of anhydrous toluene is mixed with 5.3 ml ofthiophenol, and it is stirred for 2 days under an atmosphere of dryargon at 23° C. It is poured into a 5% sodium hydroxide solution,extracted several times with ethyl acetate, the combined organicextracts are washed with water, saturated sodium chloride solution anddried on magnesium sulfate. The residue that is obtained afterfiltration and removal of the solvent is purified by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 19.5 g (98 mmol, 80%) of the title compound is isolatedas a crystalline solid.

Example 27d (2Z)-3-(2-Methyloxazol-4-yl)-2-fluoro-2-propenal

The solution of 26.2 g (131 mmol) of compound A, produced according toExample 27b or 3c, in 380 ml of anhydrous toluene is cooled under anatmosphere of dry argon to −78° C., mixed with 180 ml of a 1.2 Msolution of diisobutylaluminum hydride in toluene, and it is stirred for8 hours. It is mixed with water, extracted several times with ethylacetate, the combined organic extracts are washed with saturated sodiumchloride solution and dried on sodium sulfate. After filtration andremoval of the solvent, 20.1 g (128 mmol, 98%) of the title compound isisolated as a colorless oil, which is further reacted withoutpurification.

¹H-NMR (CDCl₃): δ=2.51 (3H), 6.69 (1H), 8.07 (1H), 9.32 (1H) ppm.

Example 27e(3S,4Z)-5-(2-Methyloxazol-4-yl)-1-[(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-on-3-yl]-3-hydroxy-4-fluoro-4-penten-1-one(A) and(3R,4Z)-5-(2-methyloxazol-4-yl)-1-[(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-on-3-yl]-3-hydroxy-4-fluoro-4-penten-1-one(B)

136 ml of a 2.4 molar solution of n-butyllithium in n-hexane is added indrops at −30° C. under an atmosphere of dry argon to the solution of45.8 ml of diisopropylamine in 2 l of anhydrous tetrahydrofuran, and itis stirred for 20 minutes, cooled to −70° C. and mixed within 4 hourswith the solution of 64.2 g of(4S,5R)-3-acetyl-4-methyl-5-phenyloxazolidin-2-one in 1 l oftetrahydrofuran. After 1 hour, the solution of 15.1 g (97.6 mmol) of thecompound, produced according to Example 27d, in 650 ml oftetrahydrofuran is added in drops within 2 hours, and it is stirred for16 hours at −70° C. It is poured onto a saturated ammonium chloridesolution, extracted several times with ethyl acetate, the combinedorganic extracts are washed with saturated sodium chloride solution anddried on sodium sulfate. The residue that is obtained after filtrationand removal of the solvent is separated by repeated chromatography onfine silica gel with a gradient system that consists of n-hexane, ethylacetate and ethanol. 19.9 g (53 mmol, 54%) of title compound A isisolated as a crystalline solid, and 8.2 g (22 mmol, 22%) of titlecompound B is isolated as a colorless foam.

¹H-NMR (CDCl₃) of A: δ=0.92 (3H), 2.47 (3H), 3.33 (1H), 3.50 (1H), 3.70(1H), 4.73–4.88 (2H), 5.71 (1H), 5.97 (1H), 7.26–7.48 (5H), 7.75 (1H)ppm.

¹H-NMR (CDCl₃) of B: =0.93 (3H), 2.48 (3H), 3.40 (2H), 4.73–4.90 (2H),5.70 (1H), 5.98 (1H), 7.24–7.49 (5H), 7.76 (1H) ppm.

Example 27f(3S,4Z)-5-(2-Methyloxazol-4-yl)-1-[(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-on-3-yl]-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4-fluoro-4-penten-1-one

Analogously to Example 1l, 16.2 g (43.5 mmol) of compound A that isproduced according to Example 27e is reacted, and after working-up andpurification, 15.9 g (32.5 mmol, 75%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.11 (6H), 0.88 (9H), 0.90 (3H), 2.46 (3H), 3.24 (1H),3.52 (1H), 4.77 (1H), 4.89 (1H), 5.66 (1H), 5.83 (1H), 7.23–7.48 (5H),7.74 (1H) ppm.

Example 27g(3S,4Z)-5-(2-Methyloxazol-4-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4-fluoro-4-pentenoicacid ethyl ester

Analogously to Example 22e, 15.6 g (32.6 mmol) of the compound that isproduced according to Example 27f is reacted, and after working-up andpurification, 11.4 g (32 mmol, 98%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.08 (6H), 0.88 (9H), 1.26 (3H), 2.43 (3H), 2.67 (2H),4.13 (2H), 4.71 (1H), 5.80 (1H), 7.72 (1H) ppm.

Example 27h(3S,4Z)-5-(2-Methyloxazol-4-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4-fluoro-4-penten-1-ol

Analogously to Example 22f, 11.4 g (31.9 mmol) of the compound that isproduced according to Example 27g is reacted, and after working-up andpurification, 9.16 g (29 mmol, 91%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.07 (3H), 0.10 (3H), 0.90 (9H), 1.94 (2H), 2.08 (1H),2.43 (3H), 3.73 (1H), 3.80 (1H), 4.49 (1H), 5.80 (1H), 7.71 (1H) ppm.

Example 27i(3S,4Z)-5-(2-Methyloxazol-4-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-iodo-4-fluoro-4-pentene

Analogously to Example 22g, 7.16 g (22.7 mmol) of the compound that isproduced according to Example 27h is reacted, and after working-up andpurification, 8.06 g (18.9 mmol, 83%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.09 (3H), 0.15 (3H), 0.91 (9H), 2.20 (2H), 2.46 (3H),3.23 (2H), 4.33 (1H), 5.80 (1H), 7.73 (1H) ppm.

Example 27j(3S,4Z)-5-(2-Methyloxazol-4-yl)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4-fluoro-4-pentene-1-triphenylphosphoniumiodide

Analogously to Example 22h, 8.06 g (18.9 mmol) of the compound that isproduced according to Example 27i is reacted, and after working-up andpurification, 10.7 g (15.6 mmol, 82%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.10 (3H), 0.18 (3H), 0.87 (9H), 1.97 (1H), 2.10 (1H),2.42 (3H), 3.48 (1H), 3.97 (1H), 4.86 (1H), 5.93 (1H), 7.63–7.88 (16H)ppm.

Example 27k(2S,6E/Z,9S,10Z)-9-[[(Dimethyl(1,1-dimethylethyl)silyl]oxy]-10-fluoro-11-(2-methyloxazol-4-yl)-1-(tetrahydropyran-2-yloxy)-2,6-dimethyl-undeca-6,10-diene

Analogously to Example 22i, 3.20 g (14.0 mmol) of the compound that isproduced according to Example 27j is reacted, and after working-up andpurification, 3.53 g (6.9 mmol, 49%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.08 (6H), 0.84–0.97 (12H), 1.09 (1H), 1.22–2.04(12H), 1.59+1.68 (3H), 2.30–2.49 (2H), 2.44 (3H), 3.06–3.27 (1H),3.42–3.62 (2H), 3.86 (1H), 4.19 (1H), 4.55 (1H), 5.12 (1H), 5.73 (1H),7.71 (1H) ppm.

Example 27l(2S,6E/Z,9S,10Z)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-10-fluoro-1-(2-methyloxazol-4-yl)-1-hydroxy-2,6-dimethyl-undeca-6,10-diene

Analogously to Example 1k, 3.48 g (6.83 mmol) of the compound that isproduced according to Example 27k is reacted, and after working-up andpurification, 2.28 g (5.36 mmol, 78%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.08 (6H), 0.83–0.94 (12H), 1.03 (1H), 1.21–1.70 (5H),1.58+1.68 (3H), 1.91–2.05 (2H), 2.27–2.50 (2H), 2.44 (3H), 3.37–3.52(2H), 4.19 (1H), 5.12 (1H), 5.72 (1H), 7.72 (1H) ppm.

Example 27m(2S,6E/Z,9S,10Z)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-10-fluoro-11-(2-methyloxazol-4-yl)-2,6-dimethyl-undeca-6,10-dienal

Analogously to Example in, 2.28 g (5.36 mmol) of the compound that isproduced according to Example 271 is reacted, and after working-up andpurification, 2.27 g (5.36 mmol, 100%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ 0.06 (6H), 0.90 (9H), 1.03+1.08 (3H), 1.21–1.46 (4H),1.57+1.66 (3H), 2.00 (2H), 2.21–2.42 (3H), 2.45 (3H), 4.19 (1H), 5.14(1H), 5.73 (1H), 7.71 (1H), 9.59 (1H) ppm.

Example 27n(4S(4R,5S,6S,10E/Z,13S,14Z))-4-(13-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-(prop-2-in-1-yl)-14-fluoro-15-(2-methyloxazol-4-yl)-3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10E/Z,13S,14Z))-4-(13-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-(prop-2-in-1-yl)-14-fluoro-15-(2-methyloxazol-4-yl)-3-oxo-5-hydroxy-2,6,10-trimethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1c, 1.87 g (4.41 mmol) of the compound, producedaccording to Example 27m, with(4S)-4-(2-methyl-3-oxo-7-trimethylsilyl-hept-6-in-2-yl)-2,2-dimethyl-[1,3]dioxane,which was produced according to the process described in DE 19751200.3,is reacted, and after working-up and purification, in addition tostarting material, 1.37 g (1.87 mmol, 42%) of title compound A as wellas 190 mg (0.26 mmol, 6%) of title compound B are isolated in each caseas a colorless oil.

¹H-NMR (CDCl₃) of A: δ=0.02–0.16 (15H), 0.81–0.93 (12H), 0.97–1.78(13H), 1.06 (3H), 1.39 (3H), 1.58+1.67 (3H), 1.91–2.08 (2H), 2.30–2.48(3H), 2.44 (3H), 2.55 (1H), 3.03 (1H), 3.45 (1H), 3.52 (1H), 3.88 (1H),3.99 (1H), 4.08–4.23 (2H), 5.12 (1H), 5.72 (1H), 7.72 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.01–0.12 (15H), 0.82–1.73 (18H), 0.89 (9H), 1.17(3H), 1.40 (3H), 1.58+1.67 (3H), 1.88–2.05 (2H), 2.28–2.57 (3H), 2.42(3H), 3.41 (1H), 3.59 (1H), 3.79–4.05 (3H), 4.18 (1H), 5.11 (1H), 5.72(1H), 7.70 (1H) ppm.

Example 27o(3S,6R,7S,8S,12E/Z,15S,16Z)-15-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-16-fluoro-1,3,7-trihydroxy-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1k, 2.16 g (2.94 mmol) of compound A that isproduced according to Example 27n is reacted, and after working-up andpurification, 1.47 g (2.12 mmol, 72%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.03 (6H), 0.15 (9H), 0.85–0.95 (12H), 0.98–1.80 (7H),1.15 (3H), 1.27 (3H), 1.57+1.66 (3H), 1.90–1.08 (2H), 2.30–2.45 (3H),2.49+2.51 (3H), 2.58–2.72 (2H), 2.90+3.03 (1H), 3.37–3.72 (3H), 3.88(2H), 4.07–4.22 (2H), 5.11 (1H), 5.63+5.70 (1H), 7.71 (1H) ppm.

Example 27p(3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-1,3,7,15-tetrakis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1l, 1.47 g (2.12 mmol) of the compound that isproduced according to Example 27o is reacted, and after working-up andpurification, 2.13 g (2.05 mmol, 97%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): =0.00–0.15 (33H), 0.83–0.98 (39H), 1.00–1.72 (7H), 1.07(3H), 1.26 (3H), 1.59+1.67 (3H), 1.94 (2H), 2.27–2.43 (2H), 2.43 (3H),2.51 (2H), 3.28 (1H), 3.52–3.71 (2H), 3.78 (1H), 3.88 (1H), 4.18 (1H),5.12 (1H), 5.73 (1H), 7.71 (1H) ppm.

Example 27q(3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-1-hydroxy-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1m, 2.13 g (2.05 mmol) of the compound that isproduced according to Example 27p is reacted, and after working-up andpurification, 1.47 g (1.60 mmol, 78%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00–0.15 (27H), 0.83–0.98 (30H), 1.02–1.77 (7H), 1.10(3H), 1.27 (3H), 1.59+1.68 (3H), 1.89–2.07 (3H), 2.30–2.52 (3H), 2.45(3H), 1.68 (1H), 3.27 (1H), 3.60–3.71 (2H), 3.79 (1H), 4.05–4.23 (2H),5.13 (1H), 5.73 (1H), 7.70 (1H) ppm.

Example 27r(3S,6R,7S,8S,12E/Z,15S,16Z)-16-Fluoro-5-oxo-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dienal

Analogously to Example 1n, 1.47 g (1.60 mmol) of the compound that isproduced according to Example 27q is reacted, and after working-up, 1.62g (max. 1.60 mmol) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃) of a purified sample: δ=−0.01–0.11 (27H), 0.83–0.98(30H), 1.00–1.56 (5H), 1.11 (3H), 1.28 (3H), 1.59+1.68 (3H), 1.88–2.02(2H), 2.29–2.50 (4H), 2.43 (3H), 2.58–2.71 (2H), 3.26 (1H), 3.78 (1H),4.18 (1H), 4.50 (1H), 5.12 (1H), 5.73 (1H), 7.71 (1H), 9.77 (1H) ppm.

Example 27s(3S,6R,7S,8S,12Z,15S,16Z)-16-Fluoro-5-oxo-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12E,15S,16Z)-16-fluoro-5-oxo-3,7,15-tris-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-(3-(trimethylsilyl)-prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dienoicacid (B)

Analogously to Example 22q, 1.60 g (max. 1.60 mmol) of the compound thatis produced according to Example 27r is reacted, and after working-upand purification, 601 mg (642 μmol, 40%) of title compound A as well as500 mg (534 μmol, 33%) of title compound B are isolated in each case asa colorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.04–0.19 (27H), 0.89 (27H), 0.96 (3H),1.05–2.53 (13H), 1.19 (3H), 1.26 (3H), 1.69 (3H), 2.46 (3H), 2.63 (1H),3.32 (1H), 3.71 (1H), 4.61 (1H), 4.39 (1H), 5.18 (1H), 6.08 (1H), 7.73(1H) ppm.

¹H-NMR (CDCl₃) of B: 5–0.02–0.18 (27H), 0.90 (30H), 0.99–2.67 (14H),1.21 (6H), 1.58 (3H), 2.46 (3H), 3.32 (1H), 3.74 (1H), 4.13 (1H), 4.36(1H), 5.10 (1H), 5.79 (1H), 7.72 (1H) ppm.

Example 27t(3S,6R,7S,8S,12Z,15S,16Z)-16-Fluoro-5-oxo-3,7-bis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-15-hydroxy-6-(prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 601 mg (642 μmol) of compound A that isproduced according to Example. 27s is reacted, and after working-up, 657mg (max. 642 μmol) of the title compound is isolated as a crude product,which is further reacted without purification.

Example 27u(4S,7R,8S,9S,13Z,16S(Z))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 657 mg (max. 642 μmol) of the compound thatis produced according to Example 27u is reacted, and after working-upand purification, 91 mg (124 μmol, 19%) of the title compound isisolated as a colorless oil.

Example 27v(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 91 mg (124 μmol) of the compound that isproduced according to Example 27u is reacted, and after working-up andpurification, 45 mg (89 μmol, 73%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): =1.05 (3H), 1.10 (3H), 1.20–1.42 (4H), 1.37 (3H),1.58–1.94 (2H), 1.69 (3H), 2.04 (1H), 2.20–2.84 (8H), 2.45 (3H), 3.20(1H), 3.38 (1H), 3.78 (1H), 4.20 (1H), 5.11 (1H), 5.43 (1H), 5.90 (1H),7.73 (1H) ppm.

Example 28(4S,7R,8S,9S,13E,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneExample 28a(3S,6R,7S,8S,12E,15S,16Z)-16-Fluoro-5-oxo-3,7-bis-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-15-hydroxy-6-(prop-2-in-1-yl)-4,4,8,12-tetramethyl-17-(2-methyloxazol-4-yl)-heptadeca-12,16-dienoicacid

Analogously to Example 1e, 500 mg (534 μmol) of compound B that isproduced according to Example 27f is reacted, and after working-up, 517mg (max. 534 μmol) of the title compound is isolated as crude product,which is further reacted without purification.

Example 28b(4S,7R,8S,9S,13E,16S(Z))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1q, 517 mg (534 μmol) of the compound that isproduced according to Example 28a is reacted, and after working-up andpurification, 128 mg (175 μmol, 33%) of the title compound is isolatedas a colorless oil.

Example 28c(4S,7R,8S,9S,13E,16S(Z))-4,8-Dihydroxy-16-(1-fluoro-2-(2-methyloxazol-4-yl)ethenyl)-7-(prop-2-in-1-yl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 128 mg (175 μmol) of the compound that isproduced according to Example 28b is reacted, and after working-up andpurification, 54 mg (107 mmol, 61%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.89 (1H), 0.98 (3H), 1.02 (3H), 1.20–2.23 (7H), 1.33(3H), 1.59 (3H), 2.40–2.61 (6H), 2.42 (3H), 3.57 (1H), 3.77 (1H), 3.82(1H), 3.87 (1H), 4.33 (1H), 5.08 (1H), 5.53 (1H), 5.87 (1H), 7.72 (1H)ppm.

Example 29(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 21, 41.4 mg of the title compound is obtainedfrom 5-chloro-2-methylbenzothiazole as a colorless oil.

¹H-NMR (CDCl₃): δ=1.04 (3H), 1.07 (3H), 1.24 (3H), 1.72 (3H), 1.3–1.8(3H), 1.89 (1H), 2.26–2.63 (7H), 2.84 (3H), 2.90 (2H), 3.36 (1H), 3.78(1H), 4.12 (1H), 5.05 (1H), 5.07 (1H), 5.19 (1H), 5.76 (1H), 5.88 (1H),7.34 (1H), 7.80 (1H), 7.95 (1H) ppm.

Example 30(4S,7R,8S,9S,13E,16S)-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione

Analogously to Example 22, 108.2 mg of the title compound is obtainedfrom 5-chloro-2-methylbenzothiazole as a colorless oil.

¹H-NMR (CDCl₃): δ=1.00 (3H), 1.05 (3H), 1.24 (3H), 1.66 (3H), 1.5–1.97(3H), 1.75–1.99 (2H), 2.09–2.58 (7H), 2.79 (1H), 2.83 (3H), 3.56 (1H),3.80 (1H), 3.86 (1H), 4.08 (1H), 4.49 (1H), 4.93 (1H), 5.00 (1H), 5.01(1H), 5.73 (1H), 6.03 (1H), 7.28 (1H), 7.77 (1H), 8.00 (1H) ppm.

Example 31(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(Z),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 10, 13.6 mg of title compound A and 4.5 mg oftitle compound B are obtained from 25.0 mg of the title compound that isproduced in Example 29.

¹H-NMR (CDCl₃) of title compound A: δ=0.98 (3H), 1.02 (3H), 1.23 (3H),1.32 (3H), 1.2–1.8 (7H), 2.18 (2H), 2.27 (1H), 2.43–2.69 (4H), 2.84(3H), 2.93 (1H), 3.60 (1H), 3.69 (1H), 4.21 (1H), 4.44 (1H), 5.02 (1H),5.06 (1H), 5.72 (1H), 6.19 (1H), 7.36 (1H), 7.82 (1H), 7.94 (1H) ppm.

¹H-NMR (CDCl₃) of title compound B: δ=0.98 (3H), 1.00 (3H), 1.31 (3H),1.34 (3H), 1.1–1.75 (6H), 1.83 (1H), 2.0–2.65 (6H), 2.84 (3H), 3.03(1H), 3.06 (1H), 3.28–3.43 (2H), 4.03 (1H), 4.31 (1H), 4.98 (1H), 5.03(1H), 5.75 (1H), 6.27 (1H), 7.36 (1H), 7.81 (1H), 7.97 (1H) ppm.

Example 32(1S,3S,7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 10, 17.7 mg of title compound A and 14.6 mg oftitle compound B are obtained from 60.0 mg of the title compound that isproduced in Example 30 by plate cleaning with a mixture that consists ofmethylene chloride/ethyl acetate at a 6:4 ratio.

¹H-NMR (CDCl₃) of title compound A: δ=0.96 (3H), 1.01 (3H), 1.31 (3H),1.38 (3H), 1.2–1.9 (7H), 2.01–2.15 (1H), 2.21–2.35 (3H), 2.46–2.65 (3H),2.83 (3H), 2.93 (1H), 3.47 (1H), 3.83 (1H), 4.20–4.34 (2H), 5.02 (1H),5.07 (1H), 5.79 (1H), 6.13 (1H), 7.36 (1H), 7.81 (1H), 7.96 (1H) ppm.

¹H-NMR (CDCl₃) of title compound B: δ=1.01 (3H), 1.04 (3H), 1.14 (3H),1.33 (3H), 1.1–1.75 (6H—), 2.05–2.37 (4H), 2.42–2.65 (3H), 2.84 (3H),2.88 (1H), 3.03 (1H), 3.42 (1H), 3.49 (1H), 3.79 (1H), 4.26 (1H), 5.02(1H), 5.06 (1H), 5.74 (1H), 6.12 (1H), 7.32 (1H), 7.80 (1H), 7.94 (1H)ppm.

Example 33(1S,3S,7S,10R,11R,12S,16S)-7,11-Dihydroxy-3-(2-methyl-benzoxazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzoxazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 10, 20 mg (39 μmol) of the compound that isproduced according to Example 21 is reacted, and after working-up andpurification, 11.2 mg (21 μmol, 54%) of title compound A and 2.9 mg (5.5μmol, 14%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=0.98 (3H), 1.02 (3H), 1.19–1.78 (7H), 1.22 (3H),1.30 (3H), 2.15 (2H), 2.28 (1H), 2.33–2.60 (4H), 2.64 (3H), 2.92 (1H),3.58 (1H), 3.69 (1H), 4.18 (1H), 4.29 (1H), 5.01 (1H), 5.08 (1H), 5.72(1H), 6.14 (1H), 7.31 (1H), 7.47 (1H), 7.64 (1H) ppm.

Example 34 In Vitro Activity of Epothilone Derivatives on Human TumorCell Lines

a) IC₅₀ values [nM] for the growth inhibition of human MCF-7-breast andmulti-drug-resistant NCl/ADR-carcinoma cell lines of epothilonederivatives with 13Z-unsaturated in the crystal-violet assay incomparison to Taxol.

TABLE 1 Compound MCF-7 NC1/ADR Selectivity* Taxol 3.5 >100 >28.6 Example1 30 75 2.5 Example 2 25 70 2.8 Example 9 17 41 2.4 Example 13 34 n.d.Example 15 25 n.d. Example 21 32 n.d. Example 23 11 62 5.6 Example 27 2541 1.6 *Selectivity = IC₅₀ − (NCl/ADR): IC₅₀ (MCF-7); n.d.: not yetdetermined

The compounds of applicants' invention have a significantly higheractive strength in comparison to Taxol. All the compounds according tothe invention which were tested show an action on themulti-drug-resistant cell line NCl/ADR not exhibited by Taxol.

b) IC₅₀ values [nM] for the growth inhibition of human MCF-7-breast- andmulti-drug-resistant NCl/ADR carcinoma cell lines of epothilonederivative with 13,14-α-epoxide, which was formed from the13-Z-configured double bond in the crystal-violet assay in comparison toTaxol.

TABLE 2 Compound MCF-7 NC1/ADR Selectivity* Taxol 3.5 >100 >29 Example4A 1.3 9.1 7.0 Example 5A 3.1 3.8 1.2 Example 10A 1.2 3.6 3.0 Example 252.3 11 4.8 *Selectivity = IC₅₀ − (NCl/ADR): IC₅₀ − (MCF-7)

In contrast to Taxol, all compounds of the invention show an action onthe multi-drug-resistant cell line NCl/ADR.

c) IC₅₀ values [nM] for the growth inhibition of human MCF-7-breast- andmulti-drug-resistant NCl/ADR-carcinoma cell lines of epothilonederivatives with 13,14-epoxide, which was formed from the13-E-configured double bond, in a crystal-violet assay in comparison toTaxol.

Table 3 Compound MCF-7 NCl/ADR Selectivity* Taxol 3.5 >100 >29 Example6A or B 4.3 68 15.8 Example 12A or B 40 61 1.5 Example 12B or A 4.8 5311.0 Example 26A or B 18 60 3.3 *Selectivity = IC₅₀ − (NCl/ADR): IC₅₀ −(MCF-7)

In contrast to Taxol, all compounds show an action on themulti-drug-resistant cell line NCl/ADR.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. An epothilone compound of formula I,

in which R^(1a), R^(1b) are the same or different and mean hydrogen;C₁–C₁₀ alkyl, C₆–C₁₂ aryl, or C₇–C₂₀ aralkyl, each, except hydrogen, isoptionally substituted; R^(2a) means hydrogen, C₁–C₁₀ alkyl, C₆–C₁₂ arylor C₇–C₂₀ aralkyl, each, except hydrogen, is optionally substituted;—(CH₂)_(ra)—C≡C—(CH₂)_(pa)—R^(26a); or—(CH₂)_(ra)—CH═CH—(CH₂)_(pa)—R^(26a), R^(2b) means—(CH₂)_(rb)—C≡C—(CH₂)_(pb)—R^(26b), or—(CH₂)_(rb)—CH═CH—(CH₂)_(pb)—R^(26b), ra, rb are the same or differentand mean 0 to 4, pa, pb are the same or different and mean 0 to 3,R^(3a) means hydrogen or a C₁–C₁₀ alkyl, C₆–C₁₂ aryl or C₇–C₂₀ aralkyl,each, except hydrogen, is optionally substituted, R^(3b) means OH orOPG¹⁴ where PG¹⁴ is a protective group, R¹⁴ means hydrogen, OR^(14a) orHal, where R^(14a) is hydrogen, SO₂-alkyl, SO₂-aryl or SO₂-aralkyl, R⁴means hydrogen, C₁–C₁₀ alkyl, C₆–C₁₂ aryl or C₇–C₂₀ aralkyl, each,except hydrogen, is optionally substituted Hal; OR²⁵; or CN; R²⁵ meanshydrogen or a protective group PG⁵, R²⁶, R^(26b) are the same ordifferent and mean hydrogen; C₁–C₁₀ alkyl, C₆–C₁₂ aryl or C₇–C₂₀aralkyl, each, except hydrogen, is optionally substituted C₁–C₁₀ acyl,or, if pa or pb>0, additionally a group OR²⁷, R²⁷ means hydrogen or aprotective group PG⁶, R⁵ means hydrogen, C₁–C₁₀ alkyl, C₆–C₁₂ aryl,C₇–C₂₀ aralkyl, each optionally substituted; or (CH₂)_(s)-T, whereby sstands for 1, 2, 3 or 4, T stands for OR²² or Hal, R²² stands forhydrogen or a protective group PG⁴, R⁶, R⁷ each mean a hydrogen atom, ortaken together an additional bond or an oxygen atom, G means abenzothiazolyl, benzoxazolyl or quinolinyl radical which is optionallysubstituted by halogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NH₂, —NO₂, —N₃,—CN, C₁–C₂₀ alkyl, C₁–C₂₀ acyl, or C₁–C₂₀ acyloxy groups, D-E means agroup —CH₂—CH₂—, A-Y means a group O—C(═O), or NR²⁹—C(═O), R²⁹ meanshydrogen or C₁–C₁₀ alkyl, Z means an oxygen atom, Hal means halogen,wherein, in each occurrence “PG” together means a hydroxy protectinggroup.
 2. A compound of formula I according to claim 1, wherein R^(2a)stands for a hydrogen atom.
 3. A compound of formula I according toclaim 1, wherein R^(1a) and R^(1b) in each case stand for a methylgroup.
 4. A compound of the formula I of claim 1, wherein R^(2a) ishydrogen.
 5. A compound of the formula I of claim 1, wherein R^(2a) ishydrogen and R^(2b) is allyl, prop-2-inyl, but-3-inyl or but-3-enyl. 6.A compound of the formula I of claim 1, wherein R^(3a) and R^(3b) takentogether are H/OH.
 7. A compound of the formula I of claim 1, wherein R⁴is methyl, ethyl, propyl, n-butyl, i-butyl, t-butyl or benzyl.
 8. Acompound of the formula I of claim 1, wherein R⁵ is H, C₁₋₅ alkyl or—(CH₂)_(s)-T where T is OH, F or Cl and s is 1 or
 2. 9. A compound ofthe formula I of claim 1, wherein G is a 2-methyl-benzothiazol-5-yl2-methyl-benzoxazol-5-yl or quinolin-7-yl radical.
 10. A compound ofclaim 9, wherein G is a 2-methylbenzoxazol-5-yl or2-methylbenzothiazol-5-yl radical.
 11. A compound of the formula I ofclaim 1, wherein -A—Y— is —O—C(═O) or —NR²⁹—C(═O)— wherein R²⁹ ishydrogen or C₁–C₃ alkyl.
 12. A pharmaceutical composition comprising acompound of the formula I of claim 1 and at least one pharmaceuticallyacceptable adjuvant or vehicle.
 13. A composition according to claim 12in the form of a dosage unit containing 0.1–100 mg of the compound ofthe formula I of claim
 1. 14. A method for treating ovarian, stomach,colon, adeno-, breast, lung, head or neck carcinomas, malignant melanomaor acute lymphocytic or myelocytic leukemia which comprisesadministering to a patient in need thereof a compound of the formula Iof claim
 1. 15. A method of claim 14, wherein the compound of formula Iis administered to a human in a dosage of 0.1–100 mg/day.
 16. A methodfor preparing a compound of the formula I, of claim 1, which comprises:cyclizing a compound of the formula ABC-1 or ABC-2

wherein R¹⁴, Z, R³, R⁴, D, E, R⁵, R⁶, R⁷ and G have the meaning given inclaim 1, R^(1a′), R^(1b′), R^(2a′) and R^(2b′) have the meanings givenfor R^(1a), R^(1b), R^(2a) and R^(2b) in claim 1 R¹³ means CH₂OR^(13a),CH₂-Hal, CHO, CO₂R^(13b) or COHal R^(13a) means hydrogen, SO₂-alkyl,SO₂-aryl, SO₂-aralkyl or together with R^(14a) can be —(CH₂)_(o) whereo=2 to 4 group or together with R^(14a) can be a C^(15a)R^(15b) group,R^(13b) means hydrogen, C₁–C₂₀ alkyl, C₆–C₁₂ aryl, C₇–C₂₀ aralkyl, each,except hydrogen, is optionally substituted, R^(15a), R^(15b) are thesame or different and mean hydrogen, C₁–C₁₀ alkyl, aryl, C₇–C₂₀ aralkylor together, R^(15a) and R^(15b) can be a —(CH₂)_(q) group where _(q) is3 to 6, PG^(14′) is hydrogen or a protecting group, R²⁰ means halogen,N₃, NHR²⁹, a hydroxy group, a protected hydroxy group O—PG², a protectedamino group NR²⁹PG², a C₁–C₁₀ alkylsulfonyloxy group, which optionallycan be perfluorinated, a benzoyloxy group that is optionally substitutedby C₁–C₄ alkyl, nitro, chlorine or bromine, an NR²⁹SO₂CH₃ group, anNR²⁹C(═O)CH₃ group, a CH₂—C(═O)—CH₃ group, R³⁰ means hydrogen, R³¹ meanshydroxyl, or R³⁰, R³¹ together mean an oxygen atom or a C₂–C₁₀alkylene-α,ω-dioxy group, which can be straight-chain or branched, orR³⁰, R³¹ independently mean a C₁–C₁₀ alkoxy group.
 17. The method ofclaim 16, wherein the compound of formula ABC-1 or ABC-2 is prepared byreacting an intermediate AB-1 or AB-2:

wherein V means an oxygen atom, two alkoxy groups OR¹⁷, a C₂–C₁₀alkylene-α,ω-dioxy group, which can be straight-chain or branched orH/OR¹⁶, W means an oxygen atom, two alkoxy groups OR¹⁹, aC₂–C₁₀-alkylene-α,ω-dioxy group, which can be straight-chain or branchedor H/OR¹⁸, R¹⁶, R¹⁸, independently of one another, mean hydrogen or aprotective group PG¹, R¹⁷, R¹⁹, independently of one another, meanC₁–C₂₀ alkyl optionally substituted, G′ means a benzothiazolyl,benzoxazolyl or quinolinyl radical which is optionally substituted byhalogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NH₂, —NO₂, —N₃, —CN, C₁–C₂₀alkyl, C₁–C₂₀ acyl, or C₁–C₂₀ acyloxy groups, R^(7′) means a hydrogenatom, R^(13a) means hydrogen, SO₂-alkyl, SO₂-aryl, SO₂-aralkyl ortogether a —(CH₂)_(o)—group or together a CR^(15a)R^(15b) group, R^(13b)means hydrogen, C₁–C₂₀ alkyl, C₆–C₁₂ aryl, C₇–C₂₀ aralkyl, each, excepthydrogen, is optionally substituted, R^(15a), R^(15b) are the samedifferent and mean hydrogen, C₁–C₁₀ alkyl, aryl, C₇–C₂₀ aralkyl ortogether a —(CH₂)_(q) group, R²¹ means a hydroxy group, halogen, aprotected hydroxy group OPG³, a phosphonium halide radical PPH₃ ⁺Hal⁻(Ph=phenyl; Hal—F, Cl, Br, I), a phosphonate radical P(O)(OQ)₂ (Q=C₁–C₁₀alkyl or phenyl) or a phosphine oxide radical P(O)Ph₂ (Ph=phenyl)R^(14′) means hydrogen, OR^(14a), Hal, OSO₂R^(14b), R^(14a) meanshydrogen, SO₂-alkyl, SO₂-aryl, or SO₂-aralkyl, R^(14b) means hydrogen,C₁–C₂₀ alkyl, C₆–C₁₂ aryl, C₇–C₂₀ aralkyl, each, except hydrogen, isoptionally substituted, o means 2 to 4, q means 3 to 6, and the othervariables are as defined above.
 18. The method of claim 17, wherein theintermediates AB-1 and AB-2 are prepared by reacting fragments A-1, A-2or C_(f) with fragment B_(f)

wherein R3^(a′), R^(4′) and R^(5′) have the meanings given for R^(3a),R⁴, R⁵, respectively.
 19. A compound of the formula I of claim 1, whichis:(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(2-methyl-benzothiazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;of the following formula:


20. A compound of formula I according to claim 1, selected from thegroup consisting of:(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(2-methyl-benzothiazol-5-yl)-1-aza-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.21. A compound of formula I of claim 1, wherein each protective group,defined as PG groups, is selected from alkyl- and/or aryl-substitutedsilyl, C₁–C₂₀ alkyl, C₄–C₇ cycloalkyl which optionally contains anoxygen atom in the ring, aryl, C₇–C₂₀ aralkyl, C₁–C₂₀ acyl, aroyl andC₁–C₂₀ alkoxycarbonyl.
 22. A method of claim 16, wherein each hydroxyprotective group is selected from alkyl- and/or aryl-substituted silyl,C₁–C₂₀ alkyl, C₄–C₇ cycloalkyl which optionally contains an oxygen atomin the ring, aryl, C₇–C₂₀ aralkyl, C₁–C₂₀ acyl, aroyl and C₁–C₂₀alkoxycarbonyl; and each amino protecting group is selected from Alloc-,Boc-, Z-, benzyl, f-Moc, Troc, Stabase or Benzostabase protectinggroups.
 23. A method of claim 17, wherein each hydroxy protective groupis selected from alkyl- and/or aryl-substituted silyl, C₁–C₂₀ alkyl,C₄–C₇ cycloalkyl which optionally contains an oxygen atom in the ring,aryl, C₇–C₂₀ aralkyl, C₁–C₂₀ acyl, aroyl and C₁–C₂₀ alkoxycarbonyl; andeach amino protecting group is selected from Alloc-, Boc-, Z-, benzyl,f-Moc, Troc, Stabase or Benzostabase protecting groups.
 24. A compoundof formula I according to claim 1, selected from the group consistingof: (4S, 7R, 8S, 9S, 13E/Z, 16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-en-l-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S, 13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(IS/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(but-3-in-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-oxa-5,5,9,13-tetramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(prop-2en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(prop-2-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11,12S,16R/S)-7,11-dihydroxy-10-(prop-2-in-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-en-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10(but-3-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-tetramethyl-7-(but-3-in-1-yl)-cyclohexadec-13-ene-2,6-dione;(1S/R,3S,7S,10R,11R,12S,16R/S)7,11-dihydroxy-10-(but-3-in-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;(4S,7R,8S,9S,13E/Z,16S)-4,8-dihydroxy-16-(quinolin-7-yl)-1-aza-5,5,9,13-etramethyl-7-(3-methyl-but-2-en-1-yl)-cyclohexadec-13-ene-2,6-dione; and(1S/R,3S,7S,10R,11R,12S,16R/S)-7,11-dihydroxy-10-(3-methyl-but-2-en-1-yl)-3-(quinolin-7-yl)-8,8,12,16-tetramethyl-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.